Controlled Release of Nitric Oxide And Drugs From Functionalized Macromers And Oligomers

ABSTRACT

The present invention provides NO and, optionally, drug releasing macromers and oligomers wherein the drug molecule and NO releasing moiety are linked an absorbable macromer or oligomeric chain susceptible to hydrolytic degradation and wherein the macromer or oligomer comprises of repeat units derived from safe and biocompatible molecules such as glycolic acid, lactic acid, caprolactone and p-dioxanone. Furthermore, the present invention relates to controlled release of nitric oxide (NO) and/or drug molecule from a NO and drug releasing macromer or oligomer. Moreover, the present invention also relates to medical devices, medical device coatings and therapeutic formulations comprising of nitric oxide and drug releasing macromers and oligomers of the present invention.

This Application claims is a divisional of U.S. Ser. No. 12/508,854,filed 24 Jul. 2009, which claims the priority of U.S. Ser. No.61/153,349, filed 18 Feb. 2009.

FIELD OF THE INVENTION

The present invention relates to NO and, optionally, drug moleculereleasing macromers and oligomers wherein the drug molecule and NOreleasing moiety are linked a hydrolytically degradable macromer oroligomeric chain comprising of repeat units derived from safe andbiocompatible molecules such as glycolic acid, lactic acid, caprolactoneand p-dioxanone. The present invention also relates to controlledrelease of NO and, optionally drug molecule from macromers and oligomersof the present invention. Furthermore, the present invention relates tomedical devices, medical device coatings and therapeutic formulationscomprising nitric oxide and drug releasing macromers and oligomers ofthe present invention.

The present invention relates to NO and, optionally, drug moleculereleasing macromers and oligomers wherein the drug molecule and NOreleasing moiety are linked to a hydrolytically degradable macromer oroligomeric chain comprising of repeat units derived from safe andbiocompatible molecules such as glycolic acid, lactic acid, caprolactoneand p-dioxanone. The present invention also relates to controlledrelease of NO and drug molecule from macromers and oligomers of thepresent invention. Furthermore, the present invention relates to medicaldevices, medical device coatings and therapeutic formulations comprisingnitric oxide and drug releasing macromers and oligomers of the presentinvention.

Nitric oxide (referred to herein as “NO”) is a vital biologicalmolecule. It plays a significant role in diverse biological processessuch as host defense, cardiovascular regulation, signal transduction,neurotransmission and wound healing. In addition to helping body cellsto communicate with each other by transmitting signals throughout theentire body, NO assists the immune system at fighting off bacteria anddefending against tumors. Furthermore, it helps reduce inflammation andregulate blood pressure by dilating arteries. Moreover, NO assist ingastric motility and alleviating erectile dysfunction.

NO is a well known inhibitor of platelet adhesion and activation.Continuous release of NO from surface of endothelial cells effectivelyprevents the adhesion/activation of platelets on normal blood vesselwalls. Furthermore, NO is also a potent inhibitor of smooth muscle cellproliferation, and agents that release or generate NO locally have beenproposed as systematic drugs to prevent and/or treat restenosis andthrombus formation when delivered to treatment sites inside anindividual that have come in contact with medical devices such ascardiovascular drug-eluting stents, diagnostic catheters, guide wires,guide catheters, PTCA balloon catheters (for percutaneous transluminalcoronary angioplasty) in blood vessels, in-dwelling sheaths (venous andarterial), intraaortic balloon pump catheters, intravascular sensors,extracorporeal blood loop circuits, intravenous grafts/shunts andadhesion prevention barriers including meshes. Furthermore, NO releasedfrom wound resident cells also play an important role in unique cellsignaling pathways and the re-establishment of the microcirculation asnewly vascularized tissue is formed. Moreover, NO is anti-inflammatory,which would be of value for in dwelling urethral or TPN catheters.

Medical research is rapidly discovering therapeutic applications for NOincluding the fields of vascular surgery and interventional cardiology.For example, Stents and DES cardiovascular stents have been usedclinically for treatment of occluded cardiac arteries for over fifteenyears and their use has resulted in substantial clinical benefit forcardiac patients. However, a significant problem with bare-metal stentsin clinical usage is restenosis of the artery, leading to recurrence ofthe primary cardiac symptoms and effects. Localized NO release appearsto address some of the root causes of the restenosis including: 1) thefibrinogen binding-platelet adhesion—release of platelet derived growthfactor cycle and 2) inflammation and associated release of growthfactors. NO release also addresses associated problems with undesiredsmooth muscle cell growth (Raulli et al. WO2007/053578 A2), and providesa long-term biocompatible solution to the presence of the stent bystimulating rapid endothelialization of the stent itself Stentendothelialization results in a natural cell coating for the stent thatessentially seeks to make the stent surface invisible to the blood andits components. Delayed endothelialization has been linked of late instent thrombosis, a potentially fatal event. Thus, the use of nitricoxide eluting stent coatings has many advantages over antiproliferativesdrugs, especially at the very early stages in the stent placementpathophysiology. One of the key benefits of NO is the stimulation ofendothelialization which is a primary measure of healing. Thus, rapiddivision of endothelial cells and their rapid colonization of the stentmaterial may be an ultimate safety feature in DES development. Hence,there exists a need for better technology addressing the release of NOand, optionally, additional drugs in drug-eluting stents.

Researchers have sought various ways to deliver NO to damaged tissue andto tissues and organs at risk of injury. One approach for providing atherapeutic level of NO at an injury site is to increase systemic NOlevels prophylactically. This can be accomplished by stimulatingendogenous NO production or using exogenous NO sources. Methods toregulate endogenous NO release have primarily focused on activation ofsynthetic pathways using excess amounts of NO precursors likeL-arginine, or increasing expression of nitric oxide synthase (NOS)using gene therapy. U.S. Pat. Nos. 5,945,452, 5,891,459 and 5,428,070describe sustained NO elevation using orally administrated L-arginineand/or L-lysine. However, these methods have not been proven effectivein preventing restenosis. Regulating endogenously expressed NO usinggene therapy techniques remains highly experimental and has not yetproven safe and effective. U.S. Pat. Nos. 5,268,465, 5,468,630 and5,658,565, describe various gene therapy approaches.

Exogenous NO sources such as pure NO gas are highly toxic, short-livedand relatively insoluble in physiological fluids. Consequently, systemicexogenous NO delivery is generally accomplished using organic nitratepro-drugs such as nitroglycerin tablets, intravenous suspensions, spraysand transdermal patches. The human body rapidly converts nitroglycerininto NO; however, enzyme levels and co-factors required to activate thepro-drug are rapidly depleted, resulting in drug tolerance. Moreover,systemic NO administration can have devastating side effects includinghypotension and free radical cell damage. Therefore, using organicnitrate pro-drugs to maintain systemic anti-restenotic therapeutic bloodlevels is not currently possible.

Ideally, NO should be delivered in a controlled manner specifically tothose tissues and organs that have been injured or are at risk ofinjury. Furthermore, topical NO delivery may also be a crucial componentof a new generation of wound dressings, since few controlled releasedrugs are currently available. Therefore, considerable attention hasbeen focused on localized, or site specific, NO delivery to amelioratethe disadvantages associated with systemic prophylaxis. Implantablemedical devices and/or local gene therapy techniques including medicaldevices coated with NO-releasing compounds, or vectors that deliver NOSgenes to target cells, have been evaluated. Like their systemiccounterparts, gene therapy techniques for the localized NO delivery havenot been proven safe and effective. There are still significanttechnical hurdles and safety concerns that must be overcome beforesite-specific NOS gene delivery will become a reality.

However, significant progress has been made in the field of localizedexogenous NO application. To be effective at preventing restenosis, aninhibitory therapeutic such as NO must be administered at a controlledrate for a sustained period at therapeutic levels. Consequently, anyNO-releasing medical device that releases NO at a controlled rate and isused to treat restenosis must be suitable for implantation. An idealcandidate device is the drug eluting vascular stent. Therefore, a stentthat safely provides therapeutically effective amounts of NO and a drugmolecule at a controlled rate to a precise location simultaneously wouldrepresent a significant advance in restenosis treatment and prevention.

Various compounds have been used to deliver NO therapeutically. Nitricoxide-releasing compounds suitable for in vivo applications have beendeveloped by a number of investigators. As early as 1960 it wasdemonstrated that nitric oxide gas could be reacted with amines to formNO-releasing anions having the following general formula 1 R—R′N—N(O)NOwherein R and R′ are ethyl. Salts of these compounds could spontaneouslydecompose and release NO in solution. (Chen et al. US 2008/0220048A1).

Nitric oxide-releasing compounds with sufficient stability at bodytemperatures to be useful as therapeutics were ultimately developed byKeefer et al. as described in U.S. Pat. Nos. 4,954,526, 5,039,705,5,155,137, 5,212,204, 5,250,550, 5,366,997, 5,405,919, 5,525,357 and5,650,447 and by Hrabie et al., J. Org. Chem. 1993, 58:1472-1476, all ofwhich are herein incorporated by reference.

Briefly, Hrabie et al. describes NO-releasing intramolecular salts(zwitterions) having the general formula 2 RN[N(O)NO⁻(CH₂)NH₂ ⁺R′.

The [N(O)NO]⁻ (abbreviated hereinafter as NONO) containing compoundsrelease NO via a first-order reaction that is predictable and easilyquantified. This is in sharp contrast to other known NO-releasingcompounds such as the S-nitrosothiol series as described in U.S. Pat.Nos. 5,380,758, 5,574,068 and 5,583,101. Stable NO-releasing compoundshave been coupled to amine containing polymers. U.S. Pat. No. 5,405,919describes biologically acceptable polymers that may be coupled toNO-releasing groups including polyolefins, such as polystyrene,polypropylene, polyethylene, polytetrafluoroethylene and polyvinylidene,and polyethylenimine, polyesters, polyethers, polyurethanes and thelike. Medical devices, such as arterial stents, composed of thesepolymers represent a potential means for the site-specific delivery ofNO.

Nitric oxide-donor compounds and compositions comprising them can beuseful for treating cardiovascular disorders, gastrointestinaldisorders, hepatic disorders and for inhibiting platelet adhesion weredeveloped by Nicoletta et al. (WO Patent No.2008/095841 A2). However,the Nicoletta disclosure does not relate to and also does not providemacromers and oligomers that release nitric oxide and, optionally, drugmolecule. Furthermore, the Nicoletta disclosure does not relate to andalso does not provide compositions comprising NO and drug releasingmacromers and oligomers, combinations thereof and their blends withabsorbable and non-absorbable polymers for applications in medicaldevices and medical device coatings. Moreover, the Nicoletta disclosurealso does not teach art by which the rate of release of NO can becontrolled.

There are a number of delivery methods of nitric oxide through a polymerincluding use of small molecule N-diazeniumdiolates from a pore matrix(WO 2007/053578, Raulli et al), use of N-diazeniumdiolate polymers (U.S.Pat. No. 5,405,919 and 5,525,357 Keefer et al., U.S. Pat. No. 6,703,046Fitzhugh et al), nitrosothiols (U.S. Pat. No. 6,673,891 Stamler et al.)and nitroprusside (U.S. Pat. No. 6,656,217 Herzog et al.). However,N-diazeniumdiolate small molecules and polymers have the potential toform carcinogenic nitrosamines (WO 2007/053578, Raulli et al). Thenitrosothiols have been shown to be unstable and labile to standardsterilization methods, and nitroprusside is difficult to sterilize. Bothnitrosothiols and nitroprusside require metabolism to release NO and aresubject to tolerance formation. Arnold et al. have previously reportedC-diazeniumdiolate polymers (U.S. Pat. No. 7,105,502; US Pat.Application 2005/0203069). C-daizemiumdiolate polymers were alsoreported by Kalivretenos et al. (WO 2007/053578). Chen et al (US PatentApplication 2008/0220048) reported NO releasing biodegradable polymersderived from [1,4] oxazepan-7-one suitable for use as medical devicesand coatings for medical devices. Raulli et al (WO 2007/053578)described multi-phasic nitric oxide and anti-proliferative drug elutingpolymer coatings for medical devices wherein the NO is released by a NOdonor selected from a group consisting of C-diazeniumdiolates,O-diazenium diolates, N-diazenium diolates, nitrosothiols, organicnitrates and nitrites, nitroprusside and other iron nitrosyl compounds,ruthenium/NO or other metal/NO complexes, heterocyclic N-oxides,messianic heterocycles, C-nitroso compounds, oximes, N-hydroxyguanidinesand N-hydroxyureas, and other nitric oxide releasing compounds. However,all these NO donors do not provide us with a controlled release of NO.

Polymers containing groups capable of delivering NO, for examplepolymers containing diazeniumdiolate groups (NONOate groups), have beenused to coat medical devices. Furthermore, the use of NONOates for therelease of nitric oxide to specifically treat tissue that has beeninjured or is at risk of injury during sepsis or shock has beendescribed in at least Saavedra et al. U.S. Pat. No. 5,814,656, thedisclosure of which is incorporated herein by reference. Insolublepolymeric NONOates have also been generally described in Smith et al.U.S. Pat. No. 5,519,020, the disclosure of which is also incorporatedherein by reference. These polymers were used to deliver NO to specifictissues, and results have shown that controlled release of NO to aspecific site greatly reduced the inflammation and accelerates thehealing process at that site. However, decomposition products ofNONOates under oxygenated conditions can include nitrosamines, some ofwhich may be carcinogenic. In addition, NONOates generally release NOradical, which is rapidly consumed by hemoglobin and can be toxic inindividuals with arteriosclerosis. Furthermore, the elasticity of knownNO-delivering polymers is generally inadequate, making it difficult tocoat medical devices with the polymer and deliver NO with the coateddevice under physiological conditions. Protein based polymers have ahigh solubility in blood, which results in short lifetimes. Finally,many NO-delivering polymers cannot be sterilized without loss of NO fromthe polymer and amounts of NO delivered are limiting.

There are many shortcomings associated with present methods ofdelivering NO to treatment sites. NO itself is too reactive to be usedwithout some means of stabilizing the molecule until it reaches thetreatment site. Thus, NO is generally delivered to treatment sites in anindividual by means of polymers and small molecules which release NO.However, these polymers and small molecules typically release NOrapidly. As a result, they have short shelf lives and rapidly lose theirability to deliver NO under physiological conditions. For example, thelifetime of S-nitroso-D,L-penicillamine and S-nitrosocysteine inphysiological solution is no more than about an hour. As a result of therapid rate of NO release by these compositions, it is difficult todeliver sufficient quantities of NO to a treatment site for extendedperiods of time or to control the amount of NO delivered.

Although, work has been carried out in the past to develop NO donors andNO donor drug molecules including NO donor aspirin (US PatentPublication No. 2008/0288176), the work suffers from the followingdisadvantages (a) the rate of release of nitric oxide and drug moleculecannot be controlled (b) Some of the NO donors reported so far releasetoxic and carcinogenic nitrosamines upon decomposition under oxygenatedconditions (c) Some of the NO donors release NO radical, which israpidly consumed by hemoglobin and is toxic to individuals witharteriosclerosis and (c) NO donors reported in the literature have shortlives and they rapidly lose their ability to deliver NO underphysiological conditions. In light of the above drawbacks, therefore,there is a need for new molecules and compositions capable of deliveringNO and drug to treatment sites in a controlled manner and which canovercome the aforementioned shortcomings.

The present invention overcomes the aforementioned challenges byproviding NO and drug releasing macromers and oligomers wherein therate, extent and site of release of NO and the drug molecule can becontrolled independently of each other. NO and drug releasing macromersand oligomers of the present invention have highly controllablehydrolysis profiles, increased solubility, improved bioavailability,improved efficacy and enhanced functionality. The controlled releaseprofiles represent slow, moderate and/or rapid release of drug andnitric oxide. This release may be targeted to one or more specificorgans or parts of the body. The hydrolytic degradation of some specificNO and drug releasing macromers and oligomers of the present inventiontypically releases drug molecule as such with no change in nativechemical structure and efficacy. This invention provides greater controlof the bioavailability of the drug and nitric oxide while retaining theinherent biological properties of both.

NO and drug releasing macromers and oligomers of the present inventioncomprise of a drug molecule and a NO releasing moiety linked to eachother via a hydrolytically degradable linker. This hydrolyticallydegradable linker comprises of repeat units derived from safe andbiocompatible molecules such as glycolic acid, lactic acid, p-dioxanoneand caprolactone, key components of all commercially availableabsorbable medical devices. The hydrolytic degradation rate of NO anddrug releasing macromers and oligomers of the present invention iscontrolled by the number of repeat units in the linker as well as by thechoice of the safe and biocompatible molecules from which the repeatunits are derived. For example, NO and drug releasing macromers andoligomers of the present invention comprising of degradable linkercontaining repeat units derived from glycolic acid will hydrolyze fasterthan the one comprising repeat units derived from p-dioxanone.Similarly, NO and drug releasing macromers and oligomers of the presentinvention comprising of degradable linker containing repeat unitsderived from lactic acid and caprolactone should take much longer tohydrolyze than the ones wherein the degradable linker comprises ofrepeat units derived from glycolic acid and p-dioxanone.

A biologically active substance in the context of the present inventionis a substance that can act on a cell, virus, organ or organism,including but not limited to drugs (i.e. pharmaceuticals) to create achange in the functioning of the cell, virus, organ or organism. Incertain embodiments of the invention, the biologically active substancesare organic molecules having molecular weight of about 600 or less, orto polymeric species such as proteins, nucleic acids, and the like. Abiologically active substance can be a substance used in therapy of ananimal, preferably a human. For use in the invention, a biologicallyactive substance bears, or has a functional homolog that bears, one ormore hydroxyl, amino or carboxylic acid substituents, includingfunctional derivatives such as esters, amides, methyl ethers, glycosidesand other derivatives that are apparent to those skilled in the art.

In certain embodiments, a biologically active substance has one or morearomatic rings. Phenol (hydroxybenzene) is the simplest example of aphenolic compound, but most phenolics have two or more hydroxyl groupsand are bioactive substances occurring widely in food plants that areeaten regularly by substantial numbers of animals and people and havebeen found to be safe compounds. Included in the definition ofbiologically active phenolics are poly-phenols having complexsubstitution patterns and compounds having condensed rings

Biologically active substances are well known (e.g., aspirin andcapsaicin) and have been beneficially administered to patients in needthereof for more than a century. One problem that has been associatedwith many biologically active substances is that they can be difficultto dissolve in water or the human body and can also be very difficult topolymerize. Due to the availability and numerous uses of biologicallyactive substances, it is desirable to enhance their native value by, forexample, providing compounds or combinations of compounds with aspecific controlled degradation profile or range enabling controlledrelease of the biologically active substance over an extended,controllable time range.

Although, work has been carried out in the past to develop NO donors andNO donor drug molecules including NO donor aspirin (US PatentPublication No.2008/0288176), the work suffers from the followingdisadvantages (a) the rate of release of nitric oxide and drug moleculecannot be controlled (b) Some of the NO donors reported so far releasetoxic and carcinogenic nitrosamines upon decomposition under oxygenatedconditions (c) Some of the NO donors release NO radical, which israpidly consumed by hemoglobin and is toxic to individuals witharteriosclerosis and (d) NO donors reported in the literature have shortlives and they rapidly lose their ability to deliver NO underphysiological conditions.

In light of the above drawbacks of the prior art, therefore, there is aneed for new NO releasing therapeutic agents and compositions therefromwhich are susceptible to hydrolytic degradation and release Nitric oxideand drug molecule in a controlled manner without yielding any toxic andharmful by products.

SUMMARY OF INVENTION

The present invention provides NO and, optionally, drug releasingmacromers and oligomers wherein the rate, extent and site of release ofNO and the drug molecule (if present) can be controlled independently ofeach other. NO and drug releasing macromers and oligomers of the presentinvention have highly controllable hydrolysis profiles, increasedsolubility, improved bioavailability, improved efficacy and enhancedfunctionality. The controlled release profiles represent slow, moderateand/or rapid release of drug and nitric oxide. This release may betargeted to one or more specific organs or parts of the body. Thehydrolytic degradation of some specific NO and drug releasing macromersand oligomers of the present invention releases drug molecule as suchwith no change in native chemical structure and efficacy. This inventionprovides greater control on the bioavailability of the drug and nitricoxide while retaining the inherent biological properties of both.

NO and drug releasing macromers and oligomers of the present inventioncomprise of a drug molecule and a NO releasing moiety linked to eachother via a hydrolytically degradable macromeric or oligomeric chain.This hydrolytically degradable macromeric or oligomeric chain comprisesof repeat units derived from safe and biocompatible molecules such asglycolic acid, lactic acid, p-dioxanone and caprolactone, key componentsof all commercially available absorbable medical devices.

The hydrolytic degradation rate of NO and drug releasing macromers andoligomers of the present invention is controlled by the number of repeatunits in the linker as well as by the choice of the safe andbiocompatible molecules from which the repeat units are derived. Forexample, NO and drug releasing macromers and oligomers of the presentinvention comprising of degradable linker containing repeat unitsderived from glycolic acid will hydrolyze faster than the one comprisingrepeat units derived from p-dioxanone. Similarly, NO and drug releasingmacromers and oligomers of the present invention comprising ofdegradable linker containing repeat units derived from lactic acid andcaprolactone should take much longer to hydrolyze than the ones whereinthe degradable linker comprises of repeat units derived from glycolicacid and p-dioxanone.

In one embodiment, the present invention provides nitric oxide macromersand oligomers of formula A:

-   -   wherein:

-   L is —O—, —COO— or —NH—;

-   D is:    -   (i) together or separately from L, a biologically active        substance, in which case q is 1 to 4 inclusive;    -   (ii) a moiety consisting of C, H, O, S or N, predominantly        composed of C and H, and adapted with L to terminate moiety P,        in which case q is 1 (or 2) to 4 inclusive;    -   (iii) a polyester, polyether, mixed polyester/polyether,        polyurethane or polyester polyurethane polymer formed from        monomers selected to provide at least q linkages L, where q is        an integer from 1 to 200 inclusive;

-   P is one of —[—X—]_(p)— or —[—Y—]_(p)—, wherein    -   p is independently an integer from 1 to 100 inclusive;    -   1 or more independently selected repeats X are:        -   —CH₂COO— (glycolic acid moiety);        -   —CH(CH₃)COO— (lactic acid moiety);        -   —CH₂CH₂OCH₂COO— (dioxanone moiety);        -   —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);        -   —(CH₂)_(y)COO— here y is one of the numbers 2, 3 or 4, or a            number from 6 to 24 inclusive; or        -   —(CH₂CH₂O)_(z)CH₂COO— where z is an integer between 2-24,            inclusive;    -   0 or more independently selected repeats X are:        -   any other repeat that is polyester polymerization compatible            with the above recited repeats X;    -   the order and composition of repeats X is selected to provide a        desired degradation of moiety -L-P—R;    -   1 or more independently selected repeats Y are:        -   —COCH₂O— (glycolic ester moiety);        -   —COCH(CH₃)O— (lactic ester moiety);        -   —COCH₂OCH₂CH₂O— (dioxanone ester moiety);        -   —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety);        -   —CO(CH₂)_(m)O— where m is one of the numbers 2, 3 or 4, or a            number from 6 to 24 inclusive; or,        -   —COCH₂O(CH₂CH₂O)_(n)— where n is integer between 2-24            inclusive;    -   0 or more independently selected repeats Y are:        -   any other repeat that is polyester polymerization compatible            with the above recited repeats Y;    -   the order and composition of repeats Y is selected to provide a        desired degradation of moiety -L-P—R; and

-   R is according to one of the applicable following options (a), (b)    or (c):    -   (a) where P is —[—X—]_(p), R can be an alkyl group, aryl,        alkyl-aryl, an alicyclic group or alkyl-alicyclic, substituted        with one or more —O—NO₂; and    -   (b) where P is —[—Y—]_(p), R can be —NO₂;    -   (c) where D is according to (ii) or (iii), R can be -L′D′ or        L′D′L″P′R′,        -   wherein,            -   L′ is L with opposite orientation, and D′ is D, where D                is a biologically active substance, and the linkage L′-P                is chemically consistent with the recitations for L-P;                and            -   L″ is L, P′ is P except p is p′, an integer from 1 to                20, and R′ is R according to (a) or (b);

-   wherein:    -   if D is defined by (i) and X or Y comprises —CH₂CH₂CH₂CH₂CH₂COO—        or —COCH₂CH₂CH₂CH₂CH₂O—, then p is an integer from 2 to 100        inclusive;    -   if L is —COO—, then the corresponding P is —[—X—]_(p)—, and, if        L′ is present, the last repeat X lacks the terminal O and L′ is        —O— or —NH—; and    -   if L is —NH—, then the corresponding P is —[—Y—]_(p)—, and, if        L′ is present, the last repeat Y lacks the terminal O and L′ is        —O— or —OC(O)—.

The inventive compounds are defined as being functionalized with thedefined X, Y and R substituents, which alter the native value orefficacy of the pre-functionalized compound by modifying the onset orlength of action thereof.

Aryls are preferably C-6 or C-10, and can be further substituted withalkyl(s). Alicyclic rings are preferably C4 to C10, and can be furthersubstituted with alkyl(s). Alkyls are preferably C2 to C6.

Integer p can be from 100 or less, 60 or less, or 40 or less, or 20 orless, or 10 or less, or 6 or less or 4 or less. Integer p can be 1 ormore, 2 or more, 3 or more, or 4 or more. Integer p can be from one ofthe lower limits to one of the upper limits here recited.

D is defined by (i) and X or Y comprises —CH₂CH₂CH₂CH₂CH₂COO— or—COCH₂CH₂CH₂CH₂CH₂O—, then in certain embodiments, p is an integer from2, 3 or 4 to one of the upper options listed above. In certainembodiments, where D is defined by (i) or (ii) and X or Y comprises—CH₂CH₂CH₂CH₂CH₂COO— or —COCH₂CH₂CH₂CH₂CH₂O—, then p is an integer from2 to 100 inclusive. In certain embodiments, where D is defined by (ii)and X or Y comprises —CH₂CH₂CH₂CH₂CH₂COO— or —COCH₂CH₂CH₂CH₂CH₂O—, thelimitations for p set forth above in this paragraph apply.

Where D is according to (ii) it can have MW of 600 or less, or 500 orless, or 400 or less, or 300 or less. By being predominately composed ofC and H it is meant that the moiety has a predominately carbon-carbonskeleton. In certain embodiments, the moiety has a carbon-carbonskeleton, optionally with oxo (O═) and hydroxy substitutions.

In certain embodiments where D is according to (iii), q can be aninteger from ll to hh, inclusive, where ll is 1, 2, 5, 10, 20 or 40, andhh is 4, 6, 10, 20, 40, 100 or 200. Where D is according to (i) or (ii),then q can be 1-3 inclusive, 1-2 or 1.

In certain embodiments, where D is according to (ii) or (iii), and R isaccording to (c), p′ is an integer that is 1 or more, 2 or more, or 3 ormore, and is 20 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6or less, or 5 or less (or a range therebetween, inclusive). In certainembodiments where D is according to (ii), D is a di-, tri- orquadra-acyl moiety, such as a succinate (from succinic acid), malonate,diglycolate, citrate, or the like.

Where R is according to (a) it can have MW of 600 or less, or 500 orless, or 400 or less, or 300 or less.

It should be noted that, except where specifically noted, the chemicalmoieties L and P above are written to insert in the formula with thesame orientation as presented (i.e., they are not reversible left toright except as specifically noted).

All individual elements within each iteration of -[-L-P—R], can beindependently selected according to the definitions herein.

In certain embodiments where D is according to (iii), some monomers ofthe polyester, polyether, mixed polyester/polyether, polyurethane orpolyester polyurethane polymer provide two linkages L (independentlyselected). In certain embodiments, monomers provide at most one linkageL.

L′, L″ and L are independently selected according to the definitionsherein. D′ and D are independently selected according to the definitionsherein. R′ and R are independently selected according to the definitionsherein.

In certain embodiments, the non-hydrocarbon functionalities in thenitric oxide macromer or oligomer, aside from D where D is a bioactivesubstance, comprise ether, ester, amide, halo, hydroxy and nitric oxide.

In one embodiment, the present invention provides nitric oxide and drugreleasing macromers and oligomers of formula I to IV:

wherein D is according to recitals (i) or (ii) for Formula A. In oneembodiment, D is according to recital (i)

In another embodiment, the present invention provides nitric oxide anddrug releasing macromers and oligomers of formula V to XIII (whereD=Drug, which is a biologically active substance):

In still another embodiment, the present invention provides NO and drugreleasing macromers and oligomers of the formula XIV to XXI:

In certain analogs of Formulas V-XXI, Drug is replaced by D, which isaccording to recitals (i) or (ii) for Formula A.

In yet still another embodiment, the present invention provides NO anddrug releasing macromers and oligomers according to formulas (I-XXI)wherein the drug molecules include but are not limited to non-steroidalanti-inflammatory drugs (NSAID) such as Naproxen, Aspirin, Ibuprofen,Indomethacin, Diclofenac and Tylenol or an antibiotic.

The present invention also provides implantable medical devices andmedical device coatings comprising an effective amount of one or more ofthe NO and drug releasing macromers and oligomers of the presentinvention physically admixed with a polymer wherein a polymer can beabsorbable or non-absorbable. Thus, the present invention provides atleast two means of enhancing the biocompatibility of the medical deviceand/or providing for in-situ controlled release of NO and drug at thetreatment site.

Exemplary embodiments of implantable medical devices and coatingscomprising of NO and drug releasing macromers and oligomers of thepresent invention include, but are not limited to cardiovasculardrug-eluting stents, diagnostic catheters, guide wires, guide catheters,PTCA balloon catheters (for percutaneous transluminal coronaryangioplasty) in blood vessels, in-dwelling sheaths (venous andarterial), intraaortic balloon pump catheters, intravascular sensors,extracorporeal blood loop circuits, intravenous grafts/shunts andadhesion prevention barriers including meshes and coatings thereforewherein NO and drug are released in-situ such that restenosis istreated, prevented or inhibited.

In another embodiment, present invention also provides a drug deliverysystem, comprising: an effective amount of one or more of the NO anddrug releasing macromers and oligomers of the present inventionphysically admixed, embedded or dispersed into the absorbable ornon-absorbable polymer and the polymer is in the form of a polymericmatrix.

In still another embodiment, the present invention provides ananti-inflammatory or anti-oxidant or antimicrobial or a pharmaceuticalcomposition comprising an effective amount of one or more of the NO anddrug releasing macromers and oligomers of the present invention whereinsaid composition is in a form suitable for oral, enteral, parenteral,topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, orvaginal administration.

In yet another embodiment, the present invention provides a method forthe treatment of diseases including but not limited to cancer andcardiovascular diseases which comprise administering to a subject inneed thereof by means of controlled drug delivery a therapeuticallyeffective amount of one or more of the NO and drug releasing macromersand oligomers of the present invention.

In still another embodiment, the present invention provides a pendantpolymer or oligomer providing monomer according to formula B or C:

wherein the component elements, excepting A and B, are consistent withthe pendant moieties associated with D as defined by (iii). A and B areindependently —OH, —NH₂ or —CO₂H.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Where L is a component of a biologically active substance, and when L is—O—, the biologically active substance typically has a hydroxyincorporating that oxygen, or is provided as an acyl derivative of thehydroxy. In this case, formula A where P is —[—Y—]_(p)— tends to provideforms that regenerate the hydroxy. Where P is —[—X—]_(p)—, it tends toprovide forms including ether acids upon hydrolysis.

Where L is a component of a biologically active substance, and when L is—COO—, the biologically active substance typically has a carboxylic acidor salt thereof incorporating that moiety, or is provided as an esterderivative.

Where L is a component of a biologically active substance, and when L is—NH—, the biologically active substance typically has an amine or saltthereof incorporating that moiety, or is provided as an amidederivative.

It will be understood that the macromer or oligomer segments of formulaA (or formula B or C described below) contain one or more repeats ofGroup A:

-   -   —CH₂COO— (glycolic acid moiety); —CH(CH₃)COO— (lactic acid        moiety);    -   —CH₂CH₂OCH₂COO— (dioxanone moiety); —CH₂CH₂CH₂CH₂CH₂COO—        (caprolactone moiety); —(CH₂)_(y)COO—; or —(CH₂CH₂O)_(z)CH₂COO—;        or    -   —COCH₂O— (glycolic ester moiety); —COCH(CH₃)O— (lactic ester        moiety);    -   —COCH₂OCH₂CH₂O— (dioxanone ester moiety); —COCH₂CH₂CH₂CH₂CH₂O—        (caprolactone ester moiety); —CO(CH₂)_(m)O—; or        —COCH₂O(CH₂CH₂O)_(n)—.

The presence of the above monomers tends to assure that a usefuldegradation profile will be obtained. However, it will be understoodthat additional, compatible monomers can be included in the macromer oroligomer segments. These can be identified by one of ordinary skill. Incertain embodiments, the Group A repeats the majority of repeats. Incertain embodiments, the Group A repeats comprise 60% or more, or 70% ormore, or 80% or more, or 90% or more, or 95% or more of the number ofrepeats. In certain embodiments, the number of non-Group A repeats isless than half the repeats, and no more than 1, or 2, or 3.

In certain embodiments, the macromer or oligomer segments of formula A(or formula B or C described below) contain one or more repeats of GroupB:

-   -   —CH₂COO— (glycolic acid moiety); —CH(CH₃)COO— (lactic acid        moiety);    -   —CH₂CH₂OCH₂COO— (dioxanone moiety); —CH₂CH₂CH₂CH₂CH₂COO—        (caprolactone moiety); —(CH₂)_(y)COO— where y is one of the        numbers 2, 3 or 4; or    -   —(CH₂CH₂O)_(z)CH₂COO— where z is an integer between 2-24        inclusive; or    -   —COCH₂O— (glycolic ester moiety); —COCH(CH₃)O— (lactic ester        moiety);    -   —COCH₂OCH₂CH₂O— (dioxanone ester moiety); —COCH₂CH₂CH₂CH₂CH₂O—        (caprolactone ester moiety); —CO(CH₂)_(m)O— where m is one of        the numbers 2, 3 or 4;    -   or —COCH₂O(CH₂CH₂O)_(n)—.

In certain embodiments, the Group B repeats the majority of repeats. Incertain embodiments, the Group B repeats comprise 60% or more, or 70% ormore, or 80% or more, or 90% or more, or 95% or more of the number ofrepeats. In certain embodiments, the number of non-Group B repeats isless than half the repeats, and no more than 1, or 2, or 3.

In certain embodiments, the macromer or oligomer segments of formula A(or formula B or C described below) contain one or more repeats of GroupC:

-   -   —CH₂COO— (glycolic acid moiety); —CH(CH₃)COO— (lactic acid        moiety);    -   —CH₂CH₂OCH₂COO— (dioxanone moiety); or —CH₂CH₂CH₂CH₂CH₂COO—        (caprolactone moiety);    -   —COCH₂O— (glycolic ester moiety); —COCH(CH₃)O— (lactic ester        moiety);    -   —COCH₂OCH₂CH₂O— (dioxanone ester moiety); or        —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety).

In certain embodiments, the Group C repeats the majority of repeats. Incertain embodiments, the Group C repeats comprise 60% or more, or 70% ormore, or 80% or more, or 90% or more, or 95% or more of the number ofrepeats. In certain embodiments, the number of non-Group C repeats isless than half the repeats, and no more than 1, or 2, or 3. In certainembodiments, p is 40 or less, or 20 or less, or 10 or less, or 8 or lessor 6 or less or 4 or less, the Group C repeats are 2 or more, 3 or more,4 or more, 5 or more, or 10 or more.

The present invention also provides NO and drug releasing macromers andoligomers wherein the macromer or oligomer is selected from thefollowing formulas (where n=2, 3 or 4):

The present invention also provides NO and drug releasing macromers andoligomers wherein D is according to (ii), such as the macromers oroligomers where D is a di-, tri- or quadra-acyl moiety. For example themacromer or oligomer can be selected from the following formulas:

The present invention also provides NO and drug releasing macromers andoligomers wherein two or more drug molecules functionalized with a NOreleasing moiety are covalently linked to each other via a hydrolysablemacromer or a oligomer.

The present invention also provides NO and drug releasing absorbable ornon-absorbable polymers including but not limited to polyesters,polyurethanes, poly(ester-amides) and combinations thereof prepared frommacromers or oligomers bearing covalently attached NO and drug releasingpendant groups.

The rate of hydrolysis of the NO and drug releasing macromers andoligomers of the present invention will depend upon a number of factors,including the number of repeat units in the linker as well as by thechoice of the safe and biocompatible molecules from which the repeatunits are derived. For example, NO and drug releasing macromers andoligomers of the present invention comprising of degradable linkercontaining repeat units derived from glycolic acid will hydrolyze fasterthan the one comprising repeat units derived from p-dioxanone.Similarly, NO and drug releasing macromers and oligomers of the presentinvention comprising of degradable linker containing repeat unitsderived from lactic acid and caprolactone should take much longer tohydrolyze than the ones wherein the degradable linker comprises ofrepeat units derived from glycolic acid and dioxanone. Furthermore, itis expected that the rate of hydrolysis will vary with variation innumber of repeat units in the degradable linker. Thus, the desired timerange may be obtained by altering number of repeat units in the linkeras well as by the choice of the safe and biocompatible molecules fromwhich the repeat units are derived.

The NO and drug releasing macromers and oligomers of the presentinvention, upon contact with body fluids including blood or the like,undergoes gradual degradation (mainly through hydrolysis) withconcomitant release of the dispersed drug for a sustained or extendedperiod. This may result in prolonged delivery (e.g., over 1-2,000 hoursor 2-800 hours) of effective amounts (e.g., 0.0001 mg/kg/hour to 10mg/kg/hour) of the drug. This dosage form may be administered as isnecessary depending on the subject being treated, the severity of theaffliction, and the judgment of the prescribing physician.

As described herein, the NO and drug releasing macromers and oligomersof the present invention are expected to be useful in medicalapplications/medical devices. Medical application/medical devices, asused herein, encompass medical and biomedical applications and includeall types of applications involved in the practice of medicine thatwould benefit from a material that decomposes harmlessly within a knownperiod of time. Examples include medical and surgical devices, whichinclude drug delivery systems (e.g., a site-specific or systemic drugdelivery systems or matrices), tissue engineering (e.g., tissuescaffold), stent coatings, stents, porous devices, implantable medicaldevices, molded articles (e.g., vascular grafts, stents, bone plates,sutures, implantable sensors, and barriers for surgical adhesionprevention), wound closure devices (e.g., surgical clips, staples, andsutures), coatings (e.g., for endoscopic instruments, sutures, stents,and needles), fibers or filaments (which may be attached to surgicalneedles or fabricated into materials including sutures or ligatures,multifilament yarn, sponges, gauze, tubes, and sheets for typing up andsupporting damaged surface abrasions), rods, films (e.g., adhesionprevention barriers), knitted products, foodstuffs, nutritionalsupplements, nutraceuticals, cosmetics, pharmaceuticals, biodegradablechewing gums, flavors, enhanced drugs, drug intermediates, cancerpreventing agents, antioxidants, controlled release preparations, andsolvents for drugs. Examples of knitted products, woven or non-woven,and molded products include: burn dressings; hernia retaining patches ormeshes; medicated dressings; facial substitutes; gauze, fabric, sheet,felt, or sponge for liver hemostasis; gauze bandages; arterial graft orsubstitutes; bandages for skin surfaces; suture knot clip; orthopedicpins, clamps, screws, and plates; clips (e.g., for vena cava); staples;hooks, buttons, and snaps; bone substitutes (e.g., mandible prosthesis);intrauterine devices (e.g., spermicidal devices); draining or testingtubes or capillaries; surgical instruments; vascular implants orsupports; vertebral discs; extracorporeal tubing for kidney andheart-lung machines; and, artificial skin.

In one embodiment, the present invention provides implantable medicaldevices comprising an effective amount of one or more of the NO and drugreleasing macromers and oligomers of the present invention physicallyadmixed with a polymer wherein a polymer can be absorbable ornon-absorbable. Absorbable polymers that can be physically admixed withnitric oxide and drug releasing macromers and oligomers of the presentinvention includes but are not limited to polyesters,poly(lactide-co-glycolide), polycaprolactone, poly(p-dioxanone),polyglycolide, polyoxaesters, poly(esterurethanes), absorbablepolyurethanes, poly(esteramides) and combinations thereof.Non-absorbable polymers that can be physically admixed with nitric oxideand drug releasing macromers and oligomers of the present inventionincludes but are not limited to polyethylene, polypropylene,polyurethanes, polyamides, polyethyleneglycols, polyacrylates,polybutylenes and combinations thereof.

In another embodiment, the present invention provides coatingcomposition for medical devices screw comprising an effective amount ofone or more of the NO and drug releasing macromers and oligomers of thepresent invention physically admixed with a polymer wherein a polymercan be absorbable or non-absorbable.

Thus, the present invention provides at least two ways of enhancing thebiocompatibility of the medical device and/or providing for in-situcontrolled release of NO and drug at the treatment site.

Exemplary embodiments of implantable medical devices and coatingscomprising of NO and drug releasing macromers and oligomers of thepresent invention include, but are not limited to cardiovasculardrug-eluting stents, diagnostic catheters, guide wires, guide catheters,PTCA balloon catheters (for percutaneous transluminal coronaryangioplasty) in blood vessels, in-dwelling sheaths (venous andarterial), intraaortic balloon pump catheters, intravascular sensors,extracorporeal blood loop circuits, intravenous grafts/shunts andadhesion prevention barriers including meshes and coatings thereforewherein NO and drug are released in-situ such that the indication soughtto be treated (e.g., restenosis) is treated, prevented, inhibited orameliorated.

For coating applications, the polymer comprising the coating compositioncan usefully exhibit an inherent viscosity, as measured in a 0.1 gramper deciliter (g/dl) of hexafluoroisopropanol (HFIP), of, for example,between about 0.05-2.0 dl/g or about 0.10-0.80 dl/g. If the inherentviscosity is too low, then the polymer may not have the integritynecessary for the preparation of films or coatings for the surfaces ofvarious surgical and medical articles. Polymers with an inherentviscosity greater than about 2.0 dl/g can be used, though in many casesit may be difficult to do so.

The amount of coating to be applied on the surface of a braided suturecan be readily determined empirically, and will depend on the particularcopolymer comprising the composition and suture chosen. In certainembodiments, the amount of coating applied to the surface of the suturemay range from about 0.5-30 percent of the weight of the coated sutureor from about 1.0-20 weight percent, or from 1-5 percent by weight. Ifthe amount of coating on the suture were too great, then there may be anincreased risk that the coating may flake off when the suture is passedthrough tissue

When the article of the present invention is a metal stent, the amountof coating applied to the surface of the article is an amount whichcreates a layer with a thickness ranging, for example, between about2-20 microns on the stent or about 4-8 microns. If the amount of coatingon the stent were such that the thickness of the coating layer wasgreater too great, or if the thickness was too low, then the desiredperformance of the stent as it is passed through tissue may not beoptimal.

When the article of the present invention is a surgical needle, theamount of coating applied to the surface of the article is an amountwhich creates a layer with a thickness ranging, for example, betweenabout 2-20 microns on the needle or about 4-8 microns. If the amount ofcoating on the needle were such that the thickness of the coating layerwas too great, or if the thickness was too low, then the desiredperformance of the needle as it is passed through tissue may not beoptimal.

In another embodiment, present invention also provides a drug deliverysystem, comprising: an effective amount of one or more of the NO and,optionally, drug releasing macromers and oligomers of the presentinvention physically admixed, embedded or dispersed into the absorbableor non-absorbable polymer and the polymer is in the form of a polymericmatrix.

In still another embodiment, the present invention provides ananti-inflammatory or anti-oxidant or antimicrobial or a pharmaceuticalcomposition comprising an effective amount of one or more of the NO and,optionally, drug releasing macromers and oligomers of the presentinvention wherein said composition is in a form suitable for oral,enteral, parenteral, topical, transdermal, ocular, vitreal, rectal,nasal, pulmonary, or vaginal administration.

The most suitable route in any given case will depend on the nature andseverity of the condition being treated and on the nature of theparticular active compound that is being used. The NO and drug releasingformulations of a pharmaceutical composition are typically admixed withone or more pharmaceutically or veterinarially acceptable carriersand/or excipients as are well known in the art.

NO and, optionally, drug releasing formulations suitable for oraladministration may be presented in discrete units, such as capsules,cachets, lozenges, or tablets, each containing a predetermined amount ofthe active compound; as a powder or granules; as a solution or asuspension in an aqueous or non-aqueous liquid; as an oil-in-water orwater-in-oil emulsion; or the like

NO and, optionally, drug releasing compositions of the present inventionsuitable for parenteral administration conveniently comprise sterileaqueous preparations of the NO releasing active compounds, whichpreparations are preferably isotonic with the blood of the intendedrecipient.

NO and, optionally, drug releasing formulations suitable for rectaladministration are preferably presented as unit dose suppositories.

NO and, optionally, drug releasing formulations suitable for ocular orvitreal administration may be presented as NO and drug releasingbioabsorbable coatings for implantable medical devices, injectables,liquids, gels, suspensions, or the like.

NO and, optionally, drug releasing formulations or compositions suitablefor topical administration to the skin preferably take the form of anointment, cream, lotion, paste, gel, spray, aerosol, oil, or the like.Examples of carriers that conventionally used include Vaseline,lanoline, polyethylene glycols, alcohols, and combination of two or morethereof.

NO and, optionally, drug releasing formulations suitable for transdermaladministration may be presented as discrete patches adapted to remain inintimate contact with the epidermis of the recipient for a prolongedperiod of time.

The NO and, optionally, drug releasing macromers and oligomers of thepresent invention may be provided in the form of foodstuffs or nutritionsupplements, such as being added to, admixed into, coated, combined orotherwise added to a foodstuff. The term foodstuff is used in its widestpossible sense and includes liquid formulations such as drinks includingdairy products, biodegradable chewing gums, and other foods, such ashealth bars, desserts, and the like. Food formulations containingcompounds of the invention can be readily prepared according to standardpractices.

NO and, optionally, drug releasing macromers and oligomers of thepresent invention used as medicaments or pharmaceuticals are typicallyadministered in a manner and amount as is conventionally practiced. See,for example, Goodman and Gilman, The Pharmaceutical Basis ofTherapeutics, 11^(th) Edition.

NO and, optionally, drug releasing macromers and oligomers of thepresent invention may have potent antioxidant activity and increasedacidity of their aromatic component, as well as the improvedbiodegradation provided by the functionalization, and thus find wideapplication in pharmaceutical and veterinary uses, in cosmetics such asmore effective skin creams to prevent skin ageing, in sun screens, infoods, health drinks, nutritional supplements, shampoos, and the like.

The present invention also provides a nitric oxide and, optionally, drugreleasing pharmaceutical composition comprising a nitric oxide and,optionally, drug releasing macromers and oligomers of the invention anda second therapeutic agent that is physically admixed, embedded ordispersed within the polymer matrix of an absorbable or non-absorbablepolymer. The invention also provides a NO releasing pharmaceuticalcomposition comprising a polymer of the invention having a secondtherapeutic agent appended to the polymer (e.g. with bonds that willhydrolyze to release the second therapeutic agent under physiologicalconditions).

Dosages

Useful dosages of the NO and, optionally, drug releasing macromers andoligomers of the present invention can be determined by comparing theirin vitro activity, and in vivo activity of the therapeutic agent inanimal models. Methods for the extrapolation of effective dosages inmice, and other animals, to humans are known to the art; for example,see U.S. Pat. No. 4,938,949. Additionally, useful dosages can bedetermined by measuring the rate of hydrolysis for a given polymer undervarious physiological conditions. The amount of NO and, optionally, drugreleasing macromers and oligomers required for use in treatment willvary not only with the particular molecule selected but also with theroute of administration, the nature of the condition being treated andthe age and condition of the patient and will be ultimately at thediscretion of the attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

In yet another embodiment, the present invention provides a method forthe treatment of diseases including but not limited to cancer andcardiovascular diseases which comprise administering to a subject inneed thereof by means of controlled drug delivery a therapeuticallyeffective amount of one or more of the NO and, optionally, drugreleasing macromers and oligomers of the present invention.

The quantity and type of NO and, optionally, drug releasing macromersand oligomers incorporated into a composition comprising the medicaldevice, medical device coating, drug delivery system, pharmaceutical,anti-inflammatory, anti-oxidative and antimicrobial formulations willvary depending on the rate and extent of release profile desired, amountof NO and, optionally, drug releasing macromers and oligomers employedand the therapeutic effect desired. The product may contain blends of NOand, optionally, drug releasing macromers and oligomers of the presentinvention to provide the desired release profile or consistency to agiven formulation.

Biologically Active Substances and Combination Therapies

The nitric oxide and, optionally, drug releasing macromers and oligomersof the present invention can also be administered in combination withother therapeutic agents that are effective to treat a given conditionto provide a combination therapy. Thus, the invention also provides amethod for treating a disease in a mammal comprising administering aneffective amount of a combination of a nitric oxide and drug releasingmacromers and oligomers of the invention and another therapeutic agent.The invention also provides a nitric oxide and drug releasingpharmaceutical composition comprising a nitric oxide and drug releasingmacromers and oligomers of the invention, another therapeutic agent, anda pharmaceutically acceptable carrier.

The NO and, optionally, drug releasing macromers and oligomers of thepresent invention are also useful for administering a combination oftherapeutic agents to an animal. Such a combination therapy can becarried out in the following ways: 1) another therapeutic agent can bephysically admixed, dispersed or embedded within the polymer matrix of aabsorbable polymer, and can be released upon degradation of the polymer;2) another therapeutic agent can be appended to an absorbable polymerwith bonds that hydrolyze to release the therapeutic agent and NO underphysiological conditions.

Another aspect of the invention provides a method by which NO and,optionally, drug releasing macromers and oligomers are prepared. Themethod involves the attachment of NO releasing moiety to a drug moleculefunctionalized with a hydrolysable linker moiety. The resultant NOreleasing functionalized drug molecules are more hydrolysable andbiodegradable than the pre-functionalized drug molecule, and providescontrolled release of the biologically active component and NO over atime period from several weeks to four years, depending on the number offactors including the number of repeat units in the linker as well as bythe choice of the safe and biocompatible molecules from which the repeatunits are derived.

Biologically active hydroxy compounds that can be used to prepare NO anddrug releasing macromers and oligomers of the present invention includeacenocoumarol, acetarsol, actinoquinol, adrenalone, alibendol,amodiaquine, anethole, balsalazide, bamethan, benserazide, bentiromide,benzarone, benzquinamide, bevantolol, bifluranol, buclosamide,bupheniode, chlorotrianisene, chloroxylenol, cianidanol, cinepazide,cinitapride, cinepazide, cinmetacin, clebopride, clemastine, clioquinol,cyclovalone, cynarine, denopamine, dextroythyroxine, diacerein,dichlorophen, dienestrol, diethylstilbestrol, diflunisal,diiodohydroxyquinoline, dilazep, dilevalol, dimestrol, dimoxyline,diosmin, dithranol, dobutamine, donepezil, dopamine, dopexamine,doxazosin, entacapone, epanolol, epimestrol, epinephrine, estradiolvalerate, estriol, estriol succinate, estrone, etamivan, etamsylate,ethaverine, ethoxzolamide, ethyl biscoumacetate, etilefrine, etiroxate,exalamide, exifone, fendosal, fenoldopam mesilate, fenoterol, fenoxedil,fenticlor, flopropione, floredil, fluorescein, folescutol, formoterol,gallopamil, gentistic acid, glaziovine, glibenclamide, glucametacin,guajacol, halquinol, hexachlorophene, hexestrol, hexobendine,hexoprenaline, hexylresorcinol, hydroxyethyl salicylate,hydroxystilbamidine isethionate, hymecromone, ifenprodil, indomethacin,ipriflavone, isoetarine, isoprenaline, isoxsuprine, itopridehydrochloride, ketobemidone, khellin, labetalol, lactylphenetidin,levodopa. levomepromazine, levorphanol, levothyroxine, mebeverine,medrylamine, mefexamide, mepacrine, mesalazine, mestranol, metaraminol,methocarbamol, methoxamine, methoxsalen, methyldopa, midodrine,mitoxantrone, morclofone, nabumetone, naproxen, nitroxoline,norfenefrine, normolaxol, octopamine, omeprazole, orciprenaline,oxilofrine, oxitriptan, oxyfedrine, oxypertine, oxyphenbutazone,oxyphenisatin acetate, oxyquinoline, papaverine, paracetanol,parethoxycaine, phenacaine, phenacetin, phenazocine, phenolphthalein,phenprocoumon, phentolamine, phloedrine, picotamide, pimobendan,prenalterol, primaquine, progabide, propanidid, protokylol,proxymetacaine, raloxifene hydrochloride, repaglinide, reproterol,rimiterol, ritodrine, salacetamide, salazosulfapyridine, salbutamol,salicylamide, salicylic acid, salmeterol, salsalate, sildenafil,silibinin, sulmetozin, tamsulosin, terazosin, terbutaline, tetroxoprim,theodrenaline, tioclomarol, tioxolone, .alpha.-tocopherol (vitamin E),tofisopam, tolcapone, tolterodine, tranilast, tretoquinol, triclosan,trimazosin, trimetazidine, trimethobenzamide, trimethoprim, trimetozine,trimetrexate glucuronate, troxipide, verapamil, vesnarinone,vetrabutine, viloxazine, warfarin, xamoterol.

Other bioactive phenolics that can be used include acacetin,4-acetamido-2-methyl-1-naphthol, acet-aminophen, albuterol, allenolicacid, aloe emodin, aloin, β-amino-4-hydroxy-3,5-di-iodohydrocinnamicacid, N-(5-amino-2-hydroxyphenyl)-benzeneacetamide, 4-amino-1-naphthol,3-aminosalicylic acid, 4-aminosalicylic acid, anacardic acid, p-anol,anthragallol, anthralin, anthranol, anthrarobin, anthrarufin, apigenin,apiin, apocynin, aspidinol, aspirin, baptigenin, benzestrol,benzoresorcinol, bisphenol a, bisphenol b, butylated hydroxylanisole,butylated hydroxytoluene, capobenic acid,trans-1-(3′-carboxy-4′-hydroxyphenyl)-2-(2″,5″-dihydroxyphenyl)ethane,catechin, chlorogenic acid, m-chlorophenol, 5-chloro-8-quinolinol,chloroxylenol, chlorquinaldol, chromo-nar, chrysin, cinametic acid,clorophene, coniferyl alcohol, p-coumaric acid, coumes-trol, coumetarol,daphnetin, datiscetin, deoxyepinephrine, 3,5-diiodothyronine,3,5-di-iodotyrosine, dimethophrine, diosmetin, diresorcinol, disoprofol,dopa, dopamine, drosophilin a, efloxate, ellagic acid, embelin, Equol,eriodictyol, esculetin, esculin, ethylnorepinephrine, ethyl vanillin,eugenol, eupatorin, fenadiazole, ferulic acid, fisetin,3-fluoro-4-hydroxyphenylacetic acid, fraxetin, fustin, galangin,gallacetophe-none, gallic acid, gardenins, genistein, gentisyl alcohol,gepefrine, geranylhydroqui-none, [6]-gingerol, gossypol, guaiacol,guaifenesin, harmalol, hematoxylin, hinderin, homoeriodictyol,homogentisic acid, homovanillic acid, hydroxyamphetamine,2-hyd-roxy-5-(2,5-dihydroxybenzylamino)-2-hydroxybenzoic acid,4-hydroxy-3-methoxy-mandelic acid, n-(p-hydroxyphenyl)glycine,hydroxyprocaine, 8-hydroxyquinoline, hypericin, irigenin, isoproterenol,isoquercitrin, isothebaine, kaempferol, liothyronine, luteolin,mangostin, 5,5′-methylenedisalicylic acid, n-methylepinephrine,metyrosine, morin, mycophenolic acid, myricetin, naringenin, nylidrin,orcinol, osalmid, osthole, oxantel, paroxypropione, pentachlorophenol,3-pentadecylcatechol, p-pentyloxy-phenol, phloretin, phloroglucinol,pinosylvine, plumbagin, pyrocatechol, pyrogallol, quercetagetin,quercetin, resacetophenone, rhamnetin, rhein, sakuranetin, salicylalcohol, salicylanilide, 4-salicyloylmorpholine, salsalate, scopoletin,scutellarein, serotonin,(3,4,5-trihydroxyphenyl)methylenepropanedinitrile, thymol, thyropropicacid, thyroxine, tiratricol, tyrosine, vanillic acid, and vanillin.

Further biologically active carboxylic acid and/or amine compounds thatcan be used to prepare a NO and drug releasing macromers and oligomersof the present invention include Acemetacin, Aceclofenac, Acediasulfone,Adipiodone, Alminoprofen, Amisulpride, Amlexanox, Amodiaquine,Amosulalol, Amoxicillin, Amsacrine, Anileridine, Azacyclonol, Baccofen,Balsalazide sodium, Bentiromide, Benzocaine, Bromopride, Bumetanide,Carprofen, Carvedilol, Carzenide, Cefprozil, Cinitapride, Cinmetacin,Clebopride, Clenbuterol, Clometacin, Cromoglicic acid, Diclofenac,Diflunisal, Eprosartan, Ethoxzolamide, Fendosal, Flufenamic acid,Furosemide, Indometacin, Iobenzamic acid, Iocarmic acid, Iocetamic acid,Iodoxamic acid, Ioglycamic acid, Iophenoic acid, Iotroxic acid,Mefenamic acid, Nadoxolol, Naproxen, Nedocromil, D-Norpseudoephedrine,paracetamol Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalateand Sarpogrelate.

In a further aspect of the present invention one can blend two or moreof the NO and drug releasing macromers and oligomers of the presentinvention.

Examples of biologically active dihydroxy compound that can be used toprepare NO and drug releasing macromers and oligomers of the presentinvention include Adrenalone, Alfuzosin, Alibendol, Amrubicin,Apomorphine, Bamethan, Benzquinamide, Bevantolol, Bifluranol, Bisacodyl,Brodimoprim, Bunazosin, Bupheniode, Carbidopa, Carbuterol, Cyclofenil,Cyclovalone, Daunorubicin, Dichlorophen, Dienestrol, Diethylstilbestrol,Dimestrol, Dithranol, Donepezil, Doxefazepam, Doxorubicin, Entacapone,Epinepheine, Epirubicin, Esomeprazole, Etamivan, Etamsylate, Etilefrine,Ezetimibe, Fenticlor, Fluorescein, Folescutol, Formoterol, Gefitinib,Hexestrol, Hexylresorcinol, Hydroxyethyl salicylate, Ifenprodil,Isoetarine, Isoxsuprine, Itopride. HCl, Khellin, Labetalol,Mitoxantrone, Morclofone, Moxaverine, Normolaxol, Omeprazole,Oxilofrine, Oxepertine, Phenacaine, Phenolphthalein, Prazosin,Tolcapone, Vesnarinone, and Vetradutine.

Examples of biologically active diamino compounds that can be used toprepare macromers/oligomers of the present invention includeAmisulpride, Amodiaquine, Amosulalol, Amoxicillin, Amsacrine,Azacyclonol, Bromopride, Carvedilol, Cefprozil, Cinitapride, Clebopride,Clenbuterol, Ethoxzolamide, Nadoxolol, and D-Norpseudoephedrine.

Examples of biologically active hydroxy/amino compounds that can be usedto prepare macromers and oligomers of the present invention includeAmisulpride, Amodiaquine, Amosulalol, Amoxicillin, Amsacrine,Azacyclonol, Bromopride, Carvedilol, Cefprozil, Cinitapride, Clebopride,Clenbuterol, Ethoxzolamide, Nadoxolol, D-Norpseudo-ephedrine, andparacetamol.

Examples of biologically active dicarboxylic acid compounds that can beused to prepare macromers and oligomers of the present invention includeAdipiodone, Cromoglicic acid, Eprosartan, Iocarmic acid, Iodoxamic acid,Ioglycamic acid, Iotroxic acid, Nedocromil.

Examples of biologically active hydroxy/carboxylic acid compounds thatcan be used to prepare macromers and oligomers of the present inventioninclude Acemetacin, Bentiromide, Cinmetacin, Clometacin, Diflunisal,Fendosal, Indometacin, Iophenoic acid, Naproxen, Repaglinide,Salazosulfapyridine, Salicylic Acid, Salsalate, and Sarpogrelate.

Examples of biologically active hydroxyl-acids useful in the presentinvention include 4-hydroxycinnamic acid, caffeic acid, chlorogenicacid, ferulic acid, sinapic acid, vanillic acid, Acemetacin,Bentiromide, Cinmetacin, Clometacin, Diflunisal, Fendosal, Indometacin,Iophenoic acid, Naproxen, Repaglinide, Salazosulfapyridine, SalicylicAcid, Salsalate, and Sarpogrelate.

Examples of biologically active amino/carboxylic acid compounds that canbe used to prepare macromers and oligomers of the present inventioninclude Aceclofenac, Acediasulfone, Alminoprofen, Amlexanox,Anileridine, Baccofen, Balsalazide sodium, Benzocaine, Bumetanide,Carprofen, Carzenide, Diclofenac, Flufenamic acid, Furosemide,Iobenzamic acid, Iocetamic acid, and Mefenamic acid.

Examples of biologically active diamino compounds useful in the presentinvention include Amisulpride, Amodiaquine, Amosulalol, Amoxicillin,Amsacrine, Azacyclonol, Bromopride, Carvedilol, Cefprozil, Cinitapride,Clebopride, Clenbuterol, Ethoxzolamide, Nadoxolol, D-Norpseudoephedrine,amino acids (L-lysine), and natural products.

Examples of naturally occurring biologically active phenolics includebergaptol, caffeic acid, capsaicin, coumarin, daidzein,2,5-dihydroxy-benzoic acid, ferulic acid, flavonoids, glycitein(isoflavone), 4-hydroxycinnamic acid, 4-hydroxy-coumarin,isopimpinellin, resveratrol, synapic acid, vanillic acid, vanillin,chalcones, soybean flavonoids and derivatives thereof.

Capsaicin is a biologically active phenolic that is the active componentof cayenne pepper. The capsaicin is an amide of vanillylamine and C₈ toC₁₃ branched fatty acids. Topical application of capsaicin stimulatesand blocks small pain fibers by depleting them of the neurotransmittersubstance P that mediates pain impulses. A cream made from 0.025%-0.075%capsaicin applied 4× daily may help peripheral neuropathic pain,post-herpetic neuralgia, trigeminal neuralgia, psoriasis andfibromyalgia. It is also useful for diabetic neuropathy, clusterheadaches, earache, osteo- and rheumatoid arthritis. Capsaicin is apowerful pain reliever.

Naproxen, paracetamol, acetaminophen and acetylsalicylic acid arebiologically active phenolics that belong to the class of drugs callednon-steroidal anti-inflammatory drugs or NSAIDs. The NSAIDs providerelief by blocking the action of prostaglandins, which are hormone-likesubstances that contribute to pain, inflammation, fever and musclecramps. Phenolic moieties, synthetic and naturally occurring, are partof many drugs.

Pendant Polymers, Misc.

Where D is according to (iii), the macromers or oligomers can be termed“pendant polymers.” These comprise polymers having pendant groupsmodified to have NO producing groups, or bioactive agents and NOproducing groups. These are often formed from monomers havingNO-releasing and/or biologically active agent-releasing moieties.Modification of polymers to provide NO-releasing and/or biologicallyactive agent-releasing moieties can also be conducted, in many casesthrough the use of appropriate protective groups for the pendantfunctionality used to attach NO-releasing and/or biologically activeagent-releasing moieties.

Monomers having NO-releasing and/or biologically active agent-releasingmoieties that can be used to form the pendant polymers of the presentinvention include but are not limited to those according to formulas Band C (above). In Formulas B and C, the terms L, L′, L″, P, P′, D′ andR′ independently have the same meaning as set forth above, and r is aninteger equal to 1 or 2. E is a moiety consisting of C, H, O, S or N,predominantly of composed of C and H. E can have a molecular weight of600 or less, or 500 or less, or 400 or less, or 300 or less. A and B areindependently —OH, —NH₂ or —CO₂H. (An acid or base form written anywherein this specification also encompasses salts thereof.) All appropriatesubdefinitions of L, L′, L″, P, P′, D′ and R′ set forth above apply tothese terms as used with the monomer formulas A and B. In other words,all embodiments of Formula A that can logically be applied to Formulas Band C are contemplated as part of the invention.

E can substantially comprise a hydrocarbon, with a trivalent orquaternary carbon directly linked by linkages comprising covalent bondsand, in most linkages, carbon to more reactive nitrogen, carbonyl oroxygen functionalities of A, B and L. In some embodiments, the linkagesfrom the trivalent or quaternary carbon to the nitrogen, carbonyl oroxygen functionalities of A, B and L are alkyl.

Examples of such monomers include, without limitation:

These diol monomers having the NO-releasing and/or biologically activeagent-releasing moieties can be reacted with acid terminated polyestersto form pendant polyesters, can be reacted with isocyanate terminatedpolyurethanes to form pendant polyurethanes, can be reacted with acidterminated polyester urethanes to form pendant polyester urethanes. Inaddition, these diol monomers having the NO-releasing and/orbiologically active agent-releasing moieties can be reacted with acidsincluding diacids, isocyanates including diisocyanates and lactonesincluding substituted lactones to form polyesters and polyurethanesbearing pendant NO-releasing and/or biologically active agent-releasingmoieties along the chain.

The D moiety is substantially exemplified by biologically active agents.These agents well exemplify the kinds of functionalities that can beused to make the macromers and oligomers of formula I.

The repeats that are polyester polymerization compatible—i.e., thosederived from monomers that can be serially attached to, orco-polymerized with, the monomers giving rise to the Group A repeats.These will be recognized by those of skill in the art, and include, forexample, diacids, diamines, diisocyanates and the like.

The macromer or oligomer is preferably applied in an effective amount.If it release NO as an active, NO is preferably released as an effectiveamount. If, in addition, a biologically active species is released, suchis preferably released as an effective amount. To treat the indicationsof the invention, an effective amount of a pharmaceutical compound willbe recognized by clinicians but includes an amount effective to treat,reduce, ameliorate, eliminate or prevent one or more symptoms of thedisease sought to be treated or the condition sought to be avoided ortreated, or to otherwise produce a clinically recognizable favorablechange in the pathology of the disease or condition.

Applicant provides herein below claims to (a) macromer or oligomer, (b)compositions thereof, (c) medical devices thereof and (d) methods oftreatment therewith. The invention includes combination of themacromer/oligomer claims that are not logically precluded. The inventionincludes group (b), (c) or (d) claims as written to depend on any of thecombinations of the macromer/oligomer claims discussed above, and anycombination of the claims of such groups (not logically precluded) aswritten to depend on any of the combinations of the macromer/oligomerclaims discussed above.

In Formulas A and B, the entire structures can be regarded as themonomer (for building a polyester, polyether, mixed polyester/polyether,polyurethane or polyester polyurethane polymer), or the elements(A)(B)EL can be regarded as the monomer. Both terminologies are usedherein, but the context makes the intended meaning clear.

In certain embodiments, the non-hydrocarbon functionalities in themonomer, aside from D where D is a bioactive substance, comprise ether,ester, amide, halo, hydroxy and nitric oxide.

The chemistry illustrated below makes use of appropriate protectinggroups to accommodate the various functionalities present. Theseprotection group strategies are well known for the amine, carboxylic,hydroxy and halo functionalities needed to practice the invention.

The definitions and examples provided in this application are notintended to be limiting, unless specifically stated. Furthermore,examples of nitric oxide and drug releasing macromers and oligomers ofthe present invention are provided for some embodiments of the currentinvention. It can be extended to other species. This selection is notmeant to limit the scope of the invention in any way. Other variationsin the procedure may be readily apparent to those skilled in the art.

EXAMPLE 1 Synthesis of 2-(6-methoxy-naphthalen-2-yl)-propionic acidbenzyloxy-carbonyl methyl ester

To a mixture of Naproxen (25 grams) and triethylamine (23 ml) in acetone(150 ml) was added benzyl chloroacetate (24 grams) drop wise, and themixture was stirred at 50° C. temperature for three hours. The reactionmixture was poured onto cold water, and crude2-(6-Methoxy-naphthalen-2-yl)-propionic acid benzyloxy-carbonyl methylester was filtered, dried and purified by recrystallizing from a mixtureof ethyl acetate:hexane to give pure2-(6-Methoxy-naphthalen-2-yl)-propionic acid benzyloxycarbonyl methylester (39 grams) as a white powder. m.p: 95.3-97.3° C. The pure productwas characterized using ¹H NMR spectroscopy in CDCl₃: δ 1.60 (d, 3H,CH₃), 3.80(m, 4H, CH and OCH₃), 4.56(q, 2H, OCH2), 5.12(q, 2H, OCH2),7.06(m, 2H, Ar), 7.30(m, 6H, Ar), 7.64(m, 3H, Ar)

EXAMPLE 2 Synthesis of 2-(6-methoxy-naphthalen-2-yl)-propionic acidcarboxymethyl ester

To a solution of 2-(6-methoxy-naphthalen-2-yl)-propionic acid benzyloxycarbonyl methyl ester (45 grams) in ethyl acetate (200 ml), was added50% wet Palladium on carbon (10%, 9 grams), and the mixture was stirredunder an atmosphere of hydrogen (4 Kg) overnight in a pressure vessel.The catalyst was removed by filtration and ethyl acetate was distilledunder vacuum. The crude product was precipitated by adding hexane,filtered, dried, and purified by recrystallization in a mixture of ethylacetate: hexane to get pure 2-(6-Methoxy-naphthalen-2-yl)-propionic acidcarboxymethyl ester (30 grams) as a white powder with a melting point of131-132.5° C. The pure product was characterized using ¹H NMRspectroscopy in CDCl₃: ¹H NMR (CDCl₃) δ 1.60(d, 3H, CH₃), 3.88(s, 1H,OCH₃), 3.94(m, 1H, CH), 4.54(q, 2H, OCH2), 7.06(m, 2H, Ar), 7.39(d, 1H,Ar), 7.64(m, 3H, Ar).

EXAMPLE 3 Synthesis of 2-(6-methoxy-naphthalen-2-yl)-propionic acid4-bromo-butoxy carbonyl methyl ester

To a mixture of 2-(6-Methoxy-naphthalen-2-yl)-propionic acidcarboxymethyl ester (30 grams) and triethylamine (21.9 ml) in acetone(200 ml) was added 1,4-dibromobutane (90 grams) drop wise, and themixture stirred at room temperature for 24 hours. The reaction mixturewas poured onto cold water, and crude2-(6-Methoxy-naphthalen-2-yl)-propionic acid 4-bromo-butoxy carbonylmethyl ester was extracted into dichloromethane. After drying oversodium sulphate, dichloromethane was distilled off under reducedpressure, and the residue was purified by column chromatography usinghexane as an eluant to get 18 grams of2-(6-Methoxy-naphthalen-2-yl)-propionic acid 4-bromo-butoxy carbonylmethyl ester as light brown syrup. The pure product was characterizedusing ¹H NMR spectroscopy in CDCl₃ ^(:) δ 1.52(d, 3H, CH₃), 1.62(m, 4H,CH₂ X₂), 3.16(t, 2H, CH₂), 3.82(m, 4H, CH and OCH₃), 3.98(t, 2H, CH₂),4.46(q, 2H, OCH2), 7.00(m, 2H, Ar), 7.30(d, 1H, Ar), 7.58(m, 3H, Ar).

EXAMPLE 4 Synthesis of 2-(6-methoxy-naphthalen-2-yl)-propionic acid3-nitrooxy-propoxy carbonyl methyl ester

To a solution of 2-(6-Methoxy-naphthalen-2-yl)-propionic acid4-bromo-butoxy carbonyl methyl ester (15 grams) in acetonitrile (150 ml)was added Silver nitrate (8.7 grams), and the mixture was left forstirring with reflux overnight. The reaction mixture was filtered andwashed with acetonitrile, dried over sodium sulphate, the solventdistilled off under reduced pressure, and the residue was purified bycolumn chromatography using hexane: ethyl acetate as eluant to get 13grams of 2-(6-Methoxy-naphthalen-2-yl)-propionic acid 3-nitrooxy-propoxycarbonyl methyl ester as a light yellow syrup. The pure product was alsocharacterized using ¹H NMR spectroscopy in CDCl₃ ^(:) 1.62(m, 7H, CH₂ X₂and CH₃), 3.92(s, 3H, OCH₃), 3.97(q, 1H, CH), 4.12(t, 2H, CH₂), 4.32(t,2H, CH₂), 4.61(s, 2H, OCH2), 7.16(m, 2H, Ar), 7.43(d, 1H, Ar), 7.73(m,3H, Ar)

EXAMPLE 5 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid

A mixture of Naproxen (500 grams) and 48% HBr solution (1500 ml) wasrefluxed for 10 Hours, poured onto ice water (3000 ml), and stirred for30 minutes. Crude 2-(6-hydroxy-naphthalen-2-yl)-propionic acid wasfiltered, dried and recrystallised from a mixture of ethyl acetate andhexane to give pure 2-(6-hydroxy-naphthalen-2-yl)-propionic acid (380grams, 81%) as a white powder with a melting point of 186-188° C.

EXAMPLE 6 Synthesis of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acidmethyl ester

To a solution of methanol (2100 ml) and sulphuric acid (84 ml) was added2-(6-Hydroxy-naphthalen-2-yl)-propionic acid (420 grams). The reactionmixture was refluxed for 6 Hours. Methanol (1000 ml) was distilled, andthe cooled reaction mass was poured onto ice water to yield crude2-(6-hydroxy-naphthalen-2-yl)-propionic acid methyl ester which wasfiltered, dried and recrystallized using a mixture of ethyl acetate:hexane to yield pure product (400 grams, 89.5% yield) as a white fluffypowder with a melting point of 89.5-92° C. The pure product wascharacterized using ¹H NMR spectroscopy in CDCl₃ δ 1.60(d, 3H, CH₃),3.70(s, 3H, Ester), 3.88(q, 1H, CH), 5.36(bs, 1H, OH), 7.08(m, 2H, Ar),7.48(m, 1H, Ar), 7.65(m, 3H, Ar).

EXAMPLE 7 Synthesis of2-[6-(2-chloro-acetoxy)-naphthalen-2-yl]-propionic acid methyl ester

To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid methylester (20 grams) and pyridine (10.3 grams) in dichloromethane (200 ml)maintained at 0-5° C. under N₂ atmosphere was added dropwise bromoacetylchloride (19.6 grams). The reaction was stirred at the same temperaturefor one hour. The reaction mixture was washed with water (500 ml) and 5%solution of sodium carbonate followed by drying over sodium sulphate anddistillation to get crude compound, which was purified by columnchromatography using hexane as eluant to get pure2-[6-(2-bromo-acetoxy)-naphthalen-2-yl]-propionic acid methyl ester (14grams) as a dark brown syrup. The pure product was characterized using¹H NMR spectroscopy in CDCl₃ δ 1.55(d,3H,CH₃), 3.65(s,3H,Ester),3.82(q,1H, CH), 4.08(s, 2H, OCH₂) 7.20(dd, 1H, Ar), 7.4(dd,1H,Ar),7.57(d, 1H,Ar), 7.72(d, 1H,Ar), 7.78(d, 1H, Ar), 7.84(d,1H, Ar).

EXAMPLE 8 Synthesis of2-[6-(2-nitrooxy-acetoxy)-naphthalen-2-yl]-propionic acid methyl ester

To a solution of 2-[6-(2-bromo-acetoxy)-naphthalen-2-yl]-propionic acidmethyl ester (14 grams) in acetonitrile (150 ml) was added silvernitrate (20.2 grams). The solution was stirred at room temperatureovernight followed by stirring at 45-50° C. for 4-6 hrs. The reactionmixture was filtered and washed with acetonitrile, dried over sodiumsulphate, and the solvent was distilled off under reduced pressure. Theresidue was purified by column chromatography using a mixture of Hexane:Ethyl acetate as eluant, followed by recrystallisation from a mixture oftoluene: hexane to get 5.5 grams2-[6-(2-Nitrooxy-acetoxy)-naphthalen-2-yl]-propionic acid methyl esteras off white powder. The pure product was characterized using ¹H NMRspectroscopy in CDCl₃ δ 1.56(d,3H,CH₃), 3.65(s, 3H,Ester), 3.90(q,1H,CH), 5.258(s, 2H, OCH₂) 7.20(dd, 1H, Ar), 7.4(dd,1H, Ar),7.57(d, 1H,Ar),7.72(d, 1H,Ar), 7.78(d, 1H, Ar), 7.84(d,1H, Ar). The pure product has amelting point of 72-74° C.

EXAMPLE 9 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid

To a mixture of Naproxen (500 grams) and 48% HBr (1500 ml) was refluxedfor 10 hours. It was poured onto ice water (3000 ml) and stirred for 30minutes. Crude 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid wasfiltered, dried and recrystallized from a mixture of ethyl acetate andhexane to yield pure product (380 grams, 81%) as a white powder with amelting point of 186-188° C.

EXAMPLE 10 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acidbenzyloxy carbonyl methyl ester

To a mixture of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid (50 grams,231.48 mmol), triethylamine (33 ml) in acetone (500 ml) was added benzylchloroacetate (45 grams) drop wise, and the mixture stirred at 50° C.temperature for three hours. The reaction mixture poured onto coldwater, crude 2-(6-hydroxy-naphthalen-2-yl)-propionic acid benzyloxycarbonyl methyl ester extracted into ethyl acetate, washed with water,dried over sodium sulphate, the solvent distilled off, and purified bycolumn chromatography with hexane: ethyl acetate as eluant to give pure2-(6-hydroxy-naphthalen-2-yl)-propionic acid benzyloxy carbonyl methylester (41 grams) as a white powder with a melting point of 104-106.5° C.The pure product was characterized using ¹H NMR spectroscopy in CDCl₃ δ1.57(d, 3H, CH₃), 3.88(q, 1H, CH), 4.60(q, 2H, OCH2), 5.10(q, 2H, OCH2),7.04(m, 2H, Ar), 7.27(m, 7H, Ar), 7.60(m, 3H, Ar),

EXAMPLE 11 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acidcarboxy methyl ester

To a solution of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid benzyloxycarbonyl methyl ester (41 grams) in ethyl acetate (400 ml) in a pressurevessel was added 50% wet palladium on carbon (10%, 9 grams) and themixture was stirred overnight under an atmosphere of hydrogen (5 Kg) ata temperature of 50° C. The catalyst was removed by filtration and ethylacetate distilled off (50%) under vacuum, and the product precipitatedby adding hexane, filtered and dried to get pure2-(6-hydroxy-naphthalen-2-yl)-propionic acid carboxy methyl ester (30grams) as a white powder with a melting point of 186-188.5° C. The pureproduct was characterized using ¹H NMR spectroscopy in CDCl₃ δ 1.60(d,3H, CH₃), 3.88(s, 1H, OCH₃), 3.94(m, 1H, CH), 4.54(q, 2H, OCH2), 7.06(m,2H, Ar), 7.39(d, 1H, Ar), 7.64(m, 3H, Ar).

EXAMPLE 12 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid4-bromo-butoxy carbonyl methyl ester

To a mixture of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid carboxymethyl ester (30 grams) and triethylamine (24 ml) in acetone (300 ml)was added dropwise 1,4-dibromo butane (96.5 grams) drop wise followed bystirring at room temperature for 24 hours. The reaction mixture waspoured onto cold water, crude 2-(6-hydroxy-naphthalen-2-yl)-propionicacid 4-bromo-butoxy carbonyl methyl ester was extracted into ethylacetate, and dried over sodium sulphate. Ethyl acetate was distilled offunder reduced pressure and the residue was purified by columnchromatography using hexane as eluant to yield 24 grams of2-(6-Hydroxy-naphthalen-2-yl)-propionic acid 4-bromo-butoxy carbonylmethyl ester as a light brown syrup. The pure product was characterizedusing ¹H NMR spectroscopy in CDCl₃ δ 1.60(d, 3H, CH₃), 1.74(m, 4H, CH₂X₂), 3.22(t, 2H, CH₂), 3.90(q, 1H, CH), 4.08(t, 2H, CH₂), 4.55(q, 2H,OCH2), 7.02(m, 2H, Ar), 7.30(d, 1H, Ar), 7.58(m, 3H, Ar)

EXAMPLE 13 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid4-bromo-butoxy carbonyl methyl ester

To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid4-bromo-butoxy carbonyl methyl ester (20 grams) in acetonitrile (200 ml)was added Silver nitrate (12.4 grams), and the mixture stirred at refluxtemperature overnight. The reaction mixture was filtered and washed withacetonitrile, dried over sodium sulphate, the solvent distilled offunder reduced pressure, residue re-dissolved in dichloromethane, and thesalts filtered off; then the organic layer was washed with water (50ml), dried over Sodium sulphate, the solvent distilled off under reducedpressure, and the residue was purified by column chromatography usinghexane: ethyl acetate as an eluant to get 17 grams of2-(6-hydroxy-naphthalen-2-yl)-propionic acid 4-nitrooxy-butoxy carbonylmethyl ester white powder.

EXAMPLE 14 Synthesis of2-[6-(2-bromo-acetoxy)-naphthalen-2-yl]-propionic acid 4-nitrooxy-butoxycarbonyl methyl ester

To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid and4-nitrooxy-butoxy carbonyl methyl ester (17 grams) and pyridine (5.7 ml)in dichloromethane (200 ml) maintained at 0-5° C. under N₂ atmospherewas added dropwise bromo acetyl bromide (5.6 ml). The reaction mixturewas stirred at the same temperature for one hour. The reaction mixturewas washed with water (25 ml) and a solution of 5% Sodium carbonate (75ml). The solution was dried over sodium sulphate and the solvent wasdistilled off to get crude2-[6-(2-Bromo-acetoxy)-naphthalen-2-yl]-propionic acid 4-nitrooxy-butoxycarbonyl methyl ester.

EXAMPLE 15 Synthesis of2-[6-(2-nitrooxy-acetoxy)-naphthalen-2-yl]-propionic acid4-nitrooxy-butoxy carbonyl methyl ester

To a solution of 2-[6-(2-Bromo-acetoxy)-naphthalen-2-yl]-propionic acid4-nitrooxy-butoxy carbonyl methyl ester (15 grams) in acetonitrile (150ml) was added silver nitrate (10 grams), and the mixture stirred at 40°C. temperature for 24 hours. The reaction mixture was filtered andwashed with acetonitrile, dried over sodium sulphate, the solventdistilled off under reduced pressure, and the residue was purified bycolumn chromatography using hexane:ethyl acetate as eluant to get 10grams of 2-[6-(2-nitrooxy-acetoxy)-naphthalen-2-yl]-propionic acid4-nitrooxy-butoxy carbonyl methyl ester as a light yellow syrup.

EXAMPLE 16 Synthesis of 2-acetoxy-benzoic acid benzyloxy carbonyl methylester

To a mixture of Aspirin (25 grams, 138.77 mmol) and triethylamine (29ml) in acetone (250 ml) was added dropwise benzyl chloro acetate (30.75grams), followed by stirring at 50° C. for five hours. The reactionmixture was poured onto cold water, crude 2-Acetoxy-benzoic acidbenzyloxy carbonyl methyl ester was filtered, dried and purified byrecrystallisation from a (1:4) mixture of chloroform: hexane to givepure 2-Acetoxy-benzoic acid benzyloxy carbonyl methyl ester (25 grams)as a white powder with a melting point of m.p: 91-92.5° C. The pureproduct was characterized using ¹H NMR spectroscopy in CDCl₃ δ 2.30(s,3H, OAc), 4.82(s, 2H, CH₂), 5.20(s, 2H, CH2), 7.10(d, 1H, Ar), 7.32(m,6H, Ar), 7.56(t, 1H, Ar), 8.18(d, 1H, Ar).

EXAMPLE 17 Synthesis of 2-acetoxy-benzoic acid carboxymethyl ester

2-Acetoxy-benzoic acid benzyloxy carbonyl methyl ester (50 grams) wasdissolved in ethyl acetate (150 ml) in a pressure vessel and 50% wetpalladium on carbon (10%, 10 grams) was added. The reaction mixture wasstirred under an atmosphere of hydrogen (4 Kg) for 14 hours. Thecatalyst was removed by filtration and ethyl acetate was distilled offunder vacuum. The crude was precipitated by adding hexane followed byfiltration, drying and purification by recrystallisation using a mixtureof ethyl acetate: hexane to yield pure 2-Acetoxy-benzoic acidcarboxymethyl ester (32 grams) as a white powder with a melting point of130-131.5° C. The pure product was characterized using ¹H NMRspectroscopy in DMSO-d₆ δ 2.28(s, 3H, OAc), 4.8(s, 2H, CH₂), 7.24(d, 1H,Ar), 7.55(t, 1H, Ar), 7.74(t, 1H, Ar), 8.10(d, 1H, Ar), 13.20 (bs, 1H,COOH).

EXAMPLE 18 Synthesis of 2-acetoxy-benzoic acid 4-bromo-butoxy carbonylmethyl ester

To a mixture of 2-acetoxy-benzoic acid carboxymethyl ester (30 grams),and triethylamine (26.5 ml) in acetone (200 ml) was added dropwise1,4-dibromo butane (109 grams). The reaction mixture was left forstirring at room temperature for 24 hours. The reaction mixture waspoured onto cold water and crude 2-acetoxy-benzoic acid 4-bromobutoxycarbonyl methyl ester was extracted into dichloromethane followed bydrying over sodium sulphate. Dichloromethane was distilled off underreduced pressure and the residue was purified by column chromatographyusing hexane as eluant to get 32 grams of 2-acetoxy-benzoic acid4-bromo-butoxy carbonyl methyl ester as a light yellow liquid. The pureproduct was characterized using ¹H NMR spectroscopy in CDCl₃ δ 1.88(m,4H, CH₂X₂), 2.32(s, 3H, OAc), 3.39(t, 2H, CH₂), 4.20(t, 2H, CH₂),4.75(s, 2H, CH₂), 7.10(d, 1H, Ar), 7.23(t, 1H, Ar), 7.50(t, 1H, Ar),8.10(d, 1H, Ar)

EXAMPLE 19 Synthesis of 2-acetoxy-benzoic acid 4-nitrooxy-butoxycarbonyl methyl ester

To a solution of 2-Acetoxy-benzoic acid 4-bromo-butoxy carbonyl methylester (20 grams) in acetonitrile (150 ml) was added silver nitrate (13.6grams). The reaction mixture was refluxed for four hours. The reactionmixture was filtered and washed with acetonitrile, dried over sodiumsulphate followed by distillation of solvent under reduced pressure. Theresidue was purified by column chromatography using hexane as eluant toget 15 grams of 2-acetoxy-benzoic acid 4-nitrooxy-butoxy carbonyl methylester as a light yellow liquid. The pure product was characterized using¹H NMR spectroscopy in CDCl₃ δ 1.80(m, 4H, CH₂X₂), 2.34(s, 3H, OAc),4.22(t, 2H, CH₂), 4.44(t, 2H, CH₂), 4.80(s, 2H, CH₂), 7.14(d, 1H, Ar),7.34(t, 1H, Ar), 7.60(t, 1H, Ar), 8.08(d, 1H, Ar.

EXAMPLE 20 Synthesis of bromo-acetic acid 2-formyl-phenyl ester

To a solution of Salicylaldehyde (50 grams) and pyridine (48.5 grams) indichloromethane (500 ml) maintained at 0-5° C. under nitrogen atmospherewas added dropwise bromoacetyl bromide (210.6 grams). The reactionmixture was stirred for one hour at the same temperature. The reactionmixture was washed with 1000 ml of water and 1500 ml of 5% sodiumbicarbonate solution, dried over sodium sulphate followed bydistillation of solvent under reduced pressure to get 60.0 grams ofbromo-acetic acid 2-formyl-phenyl ester.

EXAMPLE 21 Synthesis of nitrooxy-acetic acid 2-formyl-phenyl ester

To a solution of bromoacetic acid 2-formyl-phenyl ester (10 grams) inacetonitrile (150 ml) was added silver nitrate (14.0 grams). Thereaction mixture was stirred at room temperature for 35-38 hours. Thereaction mixture was then filtered and washed with acetonitrile, driedover sodium sulphate, and the solvent was distilled off under reducedpressure to leave the residue which was purified by columnchromatography using hexane: ethyl acetate as eluant to yield 3.0 gramsof nitrooxy-acetic acid 2-formyl-phenyl ester as brown syrup. The pureproduct was characterized using ¹H NMR spectroscopy in CDCl₃ δ 5.25(s,2H, OCH₂), 7.20 (d, 1H, Ar), 7.53(dd, 1H, Ar), 7.63(dd, 1H, Ar), 7.90(d,1H, Ar).

EXAMPLE 22 Synthesis of 2-(2-nitrooxy-acetoxy)-benzoic acid

To a solution of nitrooxyacetic acid-2-formyl-phenyl ester (3.0 grams)in acetone (50 ml) was added potassium permanganate (3 grams) at 0° C.and stirred at the same temperature for 5-6 hours. Oxalic acid (15grams) was added to the reaction mixture and the reaction mixture waswashed with acetone followed by filtration, the solution was dried oversodium sulphate and the solvent was distilled off under reducedpressure. The residue was dissolved in dichloromethane and the organiclayer was washed with water and dried over sodium sulphate. The solventwas distilled off under reduced pressure, purified by columnchromatography using a mixture of hexane: ethyl acetate as an eluant toyield 1.0 grams of product (an off white powder). The product ispurified further to yield 2-(2-nitrooxy-acetoxy)-benzoic acid.

EXAMPLE 23 Synthesis of 2-hydroxy-benzoic acid benzyloxy carbonyl methylester

To a mixture of Salicylic acid (100 grams, 724 mmol) and triethylamine(152 ml) in acetone (500 ml) was added dropwise benzyl chloroacetate(147 grams). The solution was stirred at 50° C. temperature for fourhours. The reaction mixture was poured onto cold water and the isolatedcrude 2-hydroxy-benzoic acid benzyloxy carbonyl methyl ester wasfiltered, dried and purified by recrystallising from a mixture of ethylacetate: hexane to yield pure 2-hydroxy-benzoic acid benzyloxy carbonylmethyl ester (50 grams) as a white powder with a melting point of75.5-77° C.

EXAMPLE 24 Synthesis of 2-hydroxy-benzoic acid carboxymethyl ester

To a solution of 2-hydroxy-benzoic acid benzyloxy carbonyl methyl ester(55 grams) in ethyl acetate (300 ml) in a pressure vessel was added 50%wet Palladium on carbon (10%, 15 grams). The reaction mixture wasstirred under an atmosphere of hydrogen (4 Kg) for 16 hours. Thecatalyst was removed by filtration and ethyl acetate was distilled offunder vacuum to yield crude 2-hydroxy-benzoic acid carboxymethyl ester,which was precipitated from hexane. The precipitate was filtered, driedand purified by recrystallisation from a mixture of ethyl acetate:hexane to yield 33 grams of pure 2-hydroxy-benzoic acid carboxymethylester as a white powder. The pure product was characterized using ¹H NMRspectroscopy in DMSO-d₆ δ 4.85(s, 2H, CH₂), 7.00(m, 2H, Ar), 7.55(t, 1H,Ar), 7.85(d, 1H, Ar), 10.30 (bs, 1H, OH). The pure product has a meltingpoint of 131-132.5° C.

EXAMPLE 25 Synthesis 2-hydroxy-benzoic acid 4-bromo-butoxy carbonylmethyl ester

To a mixture of 2-hydroxybenzoic acid carboxy methyl ester (33 grams),and triethylamine (36 ml) in acetone (400 ml) was added dropwise1,4-dibromo butane (146 grams). The reaction mixture was stirred at 40°C. for 16 hours. The reaction mixture was poured onto cold water toyield crude 2-Hydroxy-benzoic acid 4-bromobutoxy carbonyl methyl esterwhich was extracted into dichloro methane and dried over sodiumsulphate. The solvent was distilled off under reduced pressure and theresidue was purified by column chromatography using a mixture ofhexane:ethyl acetate as eluant to yield 40 grams of 2-hydroxybenzoicacid-4-bromo-butoxy carbonyl methyl ester as a light yellow liquid. Thepure product was characterized using ¹H NMR spectroscopy in ¹H NMR(CDCl₃) δ 1.95 (m, 4H, CH₂X₂), 3.40(t, 2H, CH₂), 4.25(t, 2H, CH₂),4.85(s, 2H, CH₂), 6.90(m, 2H, Ar), 7.5(t, 1H, Ar), 7.90(d, 1H, Ar),10.35(s, 1H, OH).

EXAMPLE 26 Synthesis of 2-hydroxy-benzoic acid 4-nitrooxy-butoxycarbonyl methyl ester

To a solution of 2-hydroxy-benzoic acid 4-bromo-butoxy carbonyl methylester (30 grams) in acetonitrile (300 ml) was added silver nitrate (30grams) and stirred at 50° C. temperature for eight hours. The reactionmixture was filtered and washed with acetonitrile, dried over sodiumsulphate, the solvent distilled off under reduced pressure, and theresidue was dissolved in dichloromethane, filtered off the salts;organic layer washed with water (50 ml), dried over sodium sulphate,distilled under vacuum, and precipitated with hexane to yield 23 gramsof 2-hydroxy-benzoic acid 4-nitrooxy-butoxy carbonyl methyl ester as anoff-white powder. The pure product was characterized using ¹H NMRspectroscopy in ¹H NMR (CDCl₃) δ 1.85(m, 4H, CH₂ X₂), 4.25(t, 2H, CH₂),4.55(t, 2H, CH₂), 4.85(s, 2H, CH₂), 6.90(m, 2H, Ar), 7.5(t, 1H, Ar),7.90(d, 1H, Ar), 10.30(s, 1H, OH). The pure product has a melting pointof 84-86.5° C.

EXAMPLE 27 Synthesis of 2-(2-bromo-acetoxy)-benzoic acid4-nitrooxy-butoxy carbonyl methyl ester

To a solution of 2-hydroxy-benzoic acid 4-nitrooxy-butoxy carbonylmethyl ester (20 grams) and pyridine (8 ml, 98.91 mmol) indichloromethane (300 ml) maintained at 0-5° C. under N₂ atmosphere wasadded dropwise bromoacetyl bromide (8 ml). The reaction mixture wasstirred at the same temperature for two hours. The reaction mixture waswashed with water (200 ml) and a 5% solution of sodium carbonate (300ml). The solution was dried over sodium sulphate and solvent wasdistilled off to yield crude 2-hydroxy-benzoic acid 4-nitrooxy-butoxycarbonyl methyl ester as light brown syrup The pure product wascharacterized using ¹H NMR spectroscopy in ¹H NMR (CDCl₃) δ 1.70(m, 4H,CH₂X₂), 4.15(t, 4H, CH₂), 4.35(s, 2H, CH₂), 4.70(s, 2H, CH₂), 7.05(d,1H, Ar), 7.30(t, 1H, Ar), 7.55(t, 1H, Ar), 8.05(d, 1H, Ar).

EXAMPLE 28 Synthesis of 2-(2-nitrooxy-acetoxy)-benzoic acid4-nitrooxy-butoxy carbonyl methyl ester

To a solution of 2-(2-bromoacetoxy)-benzoic acid-4-nitrooxy-butoxycarbonyl methyl ester (15 grams) in acetonitrile (150 ml) was addedSilver nitrate (12.2 grams). The solution was stirred at 50° C.temperature for twenty four hours. The reaction mixture was filtered,washed with acetonitrile, and dried over sodium sulphate. The solventwas distilled off under reduced pressure. The residue was dissolved indichloro methane, and the salts were filtered off. The organic layer waswashed with water (50 ml), dried over sodium sulphate, distilled undervacuum to yield 2-(2-nitrooxy-acetoxy)-benzoic acid 4-nitrooxy-butoxycarbonyl methyl ester, which was purified by column chromatography usinga mixture of hexane: ethyl acetate The product was further precipitatedwith hexane to yield 7.5 grams of 2-(2-nitrooxy-acetoxy)-benzoic acid4-nitrooxy-butoxy carbonyl methyl ester as a white powder. The pureproduct was characterized using ¹H NMR spectroscopy in ¹H NMR (CDCl₃) δδ 1.75(m, 4H, CH₂X₂), 4.20(t, 2H, CH₂), 4.45(t, 2H, CH₂), 4.80(s, 2H,CH₂), 5.30(s, 2H, CH₂), 7.15(d, 1H, Ar), 7.45(t, 1H, Ar), 7.65(t, 1H,Ar), 8.15(d, 1H, Ar).

EXAMPLE 29 Synthesis of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid2-(2-{2-[2-(6-hydroxy-naphthalen-2-yl)-propionyloxy]-acetoxy}-acetoxy)-ethoxycarbonyl methoxy carbonyl methyl ester

To a mixture of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acidcarboxymethyl ester (35 grams), triethylamine (12 ml) indimethylformamide (350 ml) at 0° C. was added dichloro linker (12.5grams). The reaction mixture was stirred at 60° C. for 21 hours. Thereaction mixture was poured onto cold water and the crude product wasextracted into ethyl acetate. The ethyl acetate extract was washed with5% sodium bicarbonate solution and water followed by drying over sodiumsulphate. Ethyl acetate was distilled off and the product was purifiedby column chromatography with hexane:ethyl acetate as eluant to yieldpure 2-(6-hydroxy-naphthalen-2-yl)-propionic acid2-(2-{2-[2-(6-hydroxy-naphthalen-2-yl)-propionyloxy]-acetoxy}-acetoxy)-ethoxycarbonyl methoxy carbonyl methyl ester (13.4 grams) as a white powderwith a melting point of 85-88° C. The pure product was characterized via¹H NMR in (CDCl₃) δ 1.55 (d, 3H, CH₃), 3.60 (s, 4H, CH₂ X₂), 3.90(q, 1H,CH), 4.55 (q, 2H, OCH₂), 5.20 (s, 1H, OH), 7.04 (d, 2H, Ar), 7.35 (d,1H, Ar), 7.55 (d, 1H, Ar), 7.62 (m, 2H, Ar).

EXAMPLE 30 Synthesis of 2-(6-bromo-hexanoyloxy)-benzoic acid benzyloxycarbonyl methyl ester

To a solution of 2-Hydroxy-benzoic acid benzyloxy carbonyl methyl ester(10 grams) and pyridine (4.2 ml) in dichloromethane (100 ml) at 0° C.under N₂ atmosphere was added dropwise 6-bromo hexanoyl chloride (9grams). The reaction mixture was stirred at the same temperature for twohours. The reaction mixture was washed with water, 5% Sodium carbonate,5% Copper Sulphate and dried over Sodium sulphate. The solvent wasdistilled off to yield crude compound which was purified by columnchromatography using a mixture of hexane and ethyl acetate. The productwas further precipitated with hexane to yield 12 grams of2-(6-Bromo-hexanoyloxy)-benzoic acid benzyloxy carbonyl methyl ester aswhite powder with a melting point of 59-60° C. The product wascharacterized via ¹H NMR (CDCl₃) δ 1.50(m, 2H, CH₂), 1.70(m, 2H, CH₂),1.85(m, 2H, CH₂), 2.55(t, 2H, CH₂), 3.30(t, 2H, CH₂), 4.70(s, 2H, CH₂),5.15(s, 2H, CH₂), 7.05(d, 1H, Ar), 7.30(m, 6H, Ar), 7.50(t, 1H, Ar),8.05(d, 1H, Ar).

EXAMPLE 31 Synthesis 2-(6-bromo-hexanoyloxy)-benzoic acid carboxy methylester

To a solution of 2-(6-bromo-hexanoyloxy)-benzoic acid benzyloxy carbonylmethyl ester (10 grams) in Ethyl acetate (200 ml) in a pressure vessel,50% wet palladium on carbon (10%, 3 grams) was added and the mixturestirred under an atmosphere of hydrogen (4 Kg) for 4 hours. The catalystwas removed by filtration and Ethyl acetate was distilled under vacuum.The product was precipitated by adding diisopropyl ether, filtered anddried to yield pure 2-(6-Bromo-hexanoyloxy)-benzoic acid carboxy methylester (4 grams) as a white powder with a melting point of 102-103° C.The final product was analyzed by ¹H NMR (CDCl₃+DMSO-d₆) δ 1.50(m, 2H,CH₂), 1.70(m, 2H, CH₂), 1.90 (m, 2H, CH₂), 2.55(t, 2H, CH₂), 3.40(t, 2H,CH₂), 4.65(s, 2H, CH₂), 7.05(d, 1H, Ar), 7.35(t, 1H, Ar), 7.55(t, 1H,Ar), 8.05(d, 1H, Ar).

EXAMPLE 32 Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid carboxymethyl ester

To a solution of 2-(6-bromo-hexanoyloxy)-benzoic acid carboxy methylester (20 grams) in acetonitrile (200 ml) at 0° C. was added silvernitrate (18 grams) and stirred at room temperature for 16 hours, laterat reflux temperature for 6 hours. The reaction mixture was filtered andwashed with acetonitrile and dried over Sodium sulphate. The solvent wasdistilled off under reduced pressure and the residue was dissolved indichloro methane, washed with water and dried over Sodium sulphate. Thedichloromethane was distilled under vacuum to get crude product whichwas purified by column chromatography using dichloromethane as eluant toyield 8 grams of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid carboxy methylester as white powder with a melting point of 87.5-89.5° C. The finalproduct was characterized by ¹H NMR (DMSO-d₆) δ 1.45(m, 2H, CH₂),1.70(m, 4H, CH₂ X2), 2.60(t, 2H, CH₂), 4.55(t, 2H, CH₂), 4.75(s, 2H,CH₂), 7.25(d, 1H, Ar), 7.45(t, 1H, Ar), 7.70(t, 1H, Ar), 8.00(d, 1H,Ar).

EXAMPLE 33 Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid(2,2,5-trimethyl-[1,3]dioxan-5-yl carbamoyl)-methyl ester

To a mixture of 2-(6-Nitrooxy-hexanoyloxy)-benzoic acid carboxy methylester (10 grams), 2,2,5-Trimethyl-[1,3]dioxan-5-yl amine (6 grams) andhydroxy benzotriazole (1.2 grams) in acetonitrile (150 ml) at 0° C. wasadded EDC.HCl (8 grams) in small lots and stirred at room temperaturefor 18 hours. The reaction mixture poured onto cold water, extractedinto ethyl acetate, dried over anhydrous Sodium sulphate, distilled andpurified by column chromatography using from a mixture of hexane: Ethylacetate to give pure 2-(6-nitrooxy-hexanoyloxy)-benzoic acid(2,2,5-trimethyl-[1,3]dioxan-5-yl carbamoyl)-methyl ester (4 grams) aslight yellow syrup. ¹H NMR (CDCl₃) δ 1.32 (s, 3H, CH₃), 1.34 (s, 3H,CH₃), 1.40 (s, 3H, CH₃), 1.45 (m, 2H, CH₂), 1.78(m, 4H, CH₂ X2), 2.64(t, 2H, CH₂), 3.62 (d, 2H, CH₂), 3.92 (d, 2H, CH₂), 4.46(t, 2H, CH₂),4.70 (s, 2H, CH₂), 5.54 (s, 1H, NH), 7.12 (d, 1H, Ar), 7.34 (t, 1H, Ar),7.64 (t, 1H, Ar), 8.05 (d, 1H, Ar).

EXAMPLE 34 Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid(2-hydroxy-1-hydroxy methyl-1-methyl-ethylcarbamoyl)-methyl ester

To a solution of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid(2,2,5-trimethyl-[1,3]dioxan-5-yl carbamoyl)-methyl ester (5.5 grams) ina mixture of Methanol (55 ml) and water (2.5 ml), was addedp-toluenesulfonic acid (0.2 grams) and stirred at room temperature for 2hours. The reaction mixture poured onto cold water, extracted with Ethylacetate, washed the organic layer with water, dried over Sodium sulphateand distilled under vacuum to get crude compound which was purified bycolumn chromatography using Hexane: Ethyl acetate as eluant to get 1grams of 2-(6-Nitrooxy-hexanoyloxy)-benzoic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethylcarbamoyl)-methyl ester as light yellow syrup. Theproduct was characterized by ¹H NMR (DMSO-d₆) δ 1.16 (s, 3H, CH₃), 1.45(m, 2H, CH₂),1.70 (m, 4H, CH₂ X2), 2.64 (t, 2H, CH₂), 3.50 (m, 4H, CH₂X2), 4.55 (t, 2H, CH₂), 4.70 (s, 2H, CH₂), 4.80 (t, 2H, OH X2), 7.25 (d,1H, Ar), 7.40 (m, 2H, Ar & NH), 7.70 (t, 1H, Ar), 8.00 (d, 1H, Ar).

EXAMPLE 35 Synthesis of 6-bromo-hexanoic acid6-(1-{2-[2-(2-{2-[6-(6-bromo-hexanoyloxy)-naphthalen-2-yl]-propionyloxy}-acetoxy)-acetoxy]ethoxycarbonylmethoxycarbonylmethoxycarbonyl}-ethyl)-naphthalen-2-yl ester

To a solution of 2-(6-hydroxy-naphthalen-2-yl)-propionic acid methylester (12 grams) and Pyridine (4.12 grams) in dichloromethane (120 ml)at 0° C. under N₂ atmosphere was added dropwise 6-bromo hexanoylchloride (14.8 grams). The reaction mixture stirred at the sametemperature for one hour. The reaction mixture was washed with water(200 ml), 5% Sodium bicarbonate solution (100 ml) and 5% Copper sulphatesolution (100 ml) followed by drying over sodium sulphate. The solventwas distilled off to yield crude product which was purified byrecrystallisation in a mixture of diisopropylether:hexane to yield6-bromo-hexanoic acid6-(1-{2-[2-(2-{2-[6-(6-bromo-hexanoyloxy)-naphthalen-2-yl]-propionyloxy}-acetoxy)-acetoxy]-ethoxycarbonylmethoxy carbonyl methoxy carbonyl}-ethyl)-naphthalen-2-yl ester (11.2grams) as white powder with a melting point of 49-50° C. The pureproduct was characterized via ^(I)H NMR in (CDCl₃) δ 1.60 (m, 5H, CH₃ &CH₂), 1.80 (m, 2H, CH₂), 1.90 (m, 2H, CH₂), 2.65 (t, 2H, CH₂), 3.45 (t,2H, CH₂), 3.70 (m, 4H, CH₂ X2), 4.00 (q, 1H, CH), 4.60 (q, 2H, CH₂),7.20 (d, 1H, Ar), 7.45 (d, 2H, Ar), 7.72 (m, 3H, Ar).

EXAMPLE 36 Synthesis of 6-nitrooxy-hexanoic acid6-(1-{2-[2(2-{2-[6-(6-nitrooxy-hexanoyloxy)-naphthalen-2-yl]-propionyloxy}-acetoxy)-acetoxy]-ethoxycarbonylmethoxycarbonyl methoxy carbonyl}-ethyl)-naphthalen-2-yl ester

To a solution of 6-bromo-hexanoic acid6-(1-{2-[2-(2-{2-[6-(6-bromo-hexanoyloxy)-naphthalen-2-yl]-propionyloxy}-acetoxy)-acetoxy]-ethoxycarbonyl methoxy carbonyl methoxy carbonyl}-ethyl)-naphthalen-2-yl ester(9 grams) in acetonitrile (180 ml) at 0° C. was added silver nitrate(4.3 grams). The reaction mixture was stirred overnight at roomtemperature followed by stirring at 60° C. for 5 hours. The reactionmixture was filtered and washed with acetonitrile and dried over sodiumsulphate. Acetonitrile was distilled off to yield crude product whichwas dissolved in chloroform. The salts were filtered off and thesolution was dried over Sodium sulphate after washing with water. Thechloroform was distilled off under reduced pressure and the residue waspurified by recrystallisation from a mixture of toluene:hexane to yield6.1 grams of 6-nitrooxy-hexanoic acid6-(1-{2-[2-(2-{2-[6-(6-nitrooxy-hexanoyloxy)-naphthalen-2-yl]-propionyloxy}-acetoxy)-acetoxy]-ethoxycarbonylmethoxy carbonyl methoxy carbonyl}-ethyl)-naphthalen-2-yl ester as whitepowder with a melting point of 45.3-47° C. The pure product wascharacterized via ¹H NMR in (CDCl₃) δ 1.55 (m, 2H, CH₂), 1.65 (d, 3H,CH₃), 1.80 (m, 4H, CH₂ X2), 2.65 (t, 2H, CH₂), 3.65 (s, 4H, CH₂ X2),4.00 (q, 1H, CH), 4.95 (t, 2H, CH₂), 4.60 (q, 2H, CH₂), 7.20 (d, 1H,Ar), 7.50 (d, 2H, Ar), 7.80 (m, 3H, Ar).

EXAMPLE 37 Synthesis of 6-bromo-hexanoic acid3-[4-(6-bromo-hexanoyloxy)-phenyl]-4-oxo-4H-chromen-7-yl ester

To a solution of daidzein (4′,7-dihydroxyisoflavone, 25 grams) indimethylformamide (250 ml) at room temperature under N₂ atmosphere wasadded 6-dromo hexanoyl chloride (68 grams). The reaction mixture wascooled to 0° C., and Pyridine (29 ml) was added dropwise to the reactionmixture. The solution was left for stirring at room temperature for 42hours. The reaction mixture was poured onto cold water followed byextraction with ethyl acetate. The ethyl acetate layer was washed with5% sodium carbonate solution followed by drying over Sodium sulphate.The ethyl acetate was distilled off to yield the crude compound and thecrude product was precipitated in hexane and washed with isopropylalcohol followed by filtration to yield 42 grams of 6-Bromo-hexanoicacid 3-[4-(6-bromo-hexanoyloxy)-phenyl]-4-oxo-4H-chromen-7-yl ester asoff-white powder with a melting point of 102-104° C. The pure productwas characterized via ^(I)H NMR in (CDCl₃) δ 1.60(m, 4H, CH₂ X₂),1.85(m, 8H, CH₂ X₄), 2.65(m, 4H, CH₂CO X₂), 3.58(t, 4H, CH₂Br X₂),7.16(m, 3H, Ar), 7.26(d, 1H, Ar), 7.60(d, 2H, Ar), 8.06(s, 1H, Ar),8.35(d, 1H, Ar).

EXAMPLE 38 Synthesis of 6-nitrooxy-hexanoic acid3-[4-(6-nitrooxy-hexanoyloxy)-phenyl]-4-oxo-4H-chromen-7-yl ester

To a solution of 6-bromo-hexanoic acid3-[4-(6-bromo-hexanoyloxy)-phenyl]-4-oxo-4H-chromen-7-yl ester (5 grams)in acetonitrile (50 ml) at 0° C. was added Silver nitrate (7.2 grams).The reaction mixture was stirred at room temperature for 4 hoursfollowed by further stirring under reflux conditions for 28 hours. Thereaction mixture was filtered and washed with acetonitrile followed bydrying over sodium sulphate. Acetonitrile was distilled off underreduced pressure and the residue was precipitated in cold water. Theprecipitate was filtered and recrystallized from a mixture of tolueneand hexane to yield 4 grams of 6-nitrooxy-hexanoic acid3-[4-(6-nitrooxy-hexanoyloxy)-phenyl]-4-oxo-4H-chromen-7-yl ester asoff-white powder with a melting point of 100-102° C. The pure productwas characterized via ^(I)H NMR in a mixture of (CDCl₃ and DMSO-d₆) δ1.60 (m, 4H, CH₂ X₂), 1.76(m, 8H, CH₂ X₄), 2.64(m, 4H, CH₂CO X₂),4.52(t, 4H, CH₂ONO₂ X₂), 7.12(d, 2H, Ar), 7.22(d, 1H, Ar), 7.32(s, 2H,Ar), 7.68(d, 2H, Ar), 8.2-18(d, 1H, Ar), 8.45(s, 1H, Ar).

EXAMPLE 39 Synthesis of 2-(6-bromo-hexanoyloxy)-benzoic acid4-nitrooxy-butoxy carbonyl methyl ester

To a solution of 2-hydroxy-benzoicacid-4-nitrooxy-butoxy carbonyl methylester (15 grams) and pyridine (6 ml) in dichloromethane (150 ml) at 0°C. under N₂ atmosphere was added 6-bromohexanoyl chloride (13.5 grams)dropwise. The reaction mixture was stirred at room temperature for 24hours. The reaction mixture was washed with water, 5% sodium carbonatesolution and 5% copper sulphate solution. The solution was dried oversodium sulphate and solvent was distilled off. The residue was purifiedby column chromatography using a mixture of hexane: ethyl acetate as aneluant to yield 16 grams of 2-(6-bromo-hexanoyloxy)-benzoic acid4-nitrooxy-butoxy carbonyl methyl ester as light yellow syrup. The pureproduct was characterized using ¹H NMR (CDCl₃) δ 1.50 (m, 2H, CH₂), 1.70(m, 6H, CH₂ X₃), 1.85 (m, 2H, CH₂), 2.55 (t, 2H, CH₂), 3.35 (t, 2H,CH₂), 4.15 (s, 2H, CH₂), 4.35 (bs, 2H, CH₂), 4.70 (s, 2H, CH₂), 7.00 (d,1H, Ar), 7.25 (t, 1H, Ar), 7.55 (t, 1H, Ar), 8.05 (d, 1H, Ar).

EXAMPLE 40 Synthesis of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid4-nitrooxy-butoxy carbonyl methyl ester

To a solution of 2-(6-bromo-hexanoyloxy)-benzoic acid 4-nitrooxy-butoxycarbonyl methyl ester (4 grams) in acetonitrile (40 ml) was added silvernitrate (2.7 grams). The reaction mixture was stirred at roomtemperature for twenty hours. The reaction mixture was filtered andwashed with acetonitrile, and dried over sodium sulphate. The solventwas distilled off under reduced pressure and the residue was dissolvedin dichloromethane. The salts were filtered off and the organic layerwas washed with water followed by drying over sodium sulphate. Thedichloromethane was distilled off under vacuum and the residue waspurified by column chromatography using a mixture of hexane: ethylacetate to yield 3 grams of 2-(2-nitrooxy-hexanoyloxy)-benzoic acid4-nitrooxy-butoxy carbonyl methyl ester as light yellow syrup. The pureproduct was characterized using ¹H NMR (CDCl₃) δ 1.50 (m, 2H, CH₂), 1.75(m, 8H, CH₂X₄), 2.55 (t, 2H, CH₂), 4.15 (t, 2H, CH₂), 4.35 (m, 4H,CH₂X₂), 4.70 (s, 2H, CH₂), 7.00 (d, 1H, Ar), 7.25 (t, 1H, Ar), 7.55 (t,1H, Ar), 8.05 (d, 1H, Ar).

EXAMPLE 41 Synthesis of Aspirin Dimer Diol

To a mixture of 2-hydroxy-benzoic acid carboxymethyl ester (22.8 grams)and triethylamine (22.6 ml) in acetone (200 ml) was added dichlorolinker (10 grams). The reaction mixture was stirred at room temperaturefor 1 hour and then refluxed for 18 hours. The reaction mixture waspoured onto cold water and crude product was extracted into ethylacetate. It was washed with 5% sodium bicarbonate solution and water,followed by drying over sodium sulphate. The solvent was distilled offand precipitated with diisopropyl alcohol to give 8 grams of pureAspirin dimer diol as a white powder with a melting point of 99-102° C.The product was characterized by ^(I)H NMR (DMSO-d₆) δ 4.40 (s, 2H,CH₂), 4.90 (s, 2H, CH₂), 5.15 (s, 2H, CH₂), 7.05 (m, 2H, Ar), 7.62 (t,1H, Ar), 7.90 (d, 1H, Ar), 10.30 (s, 1H, ArOH).

EXAMPLE 42 Synthesis of Dibromo Aspirin Dimer

To a solution of Aspirin dimer diol (8 grams) and pyridine (4.2 ml) indichloromethane (150 ml) at 0° C. under N₂ atmosphere was added dropwise6-bromohexanoyl chloride (10 grams). The reaction mixture was stirred atthe same temperature for four hours. The reaction mixture was washedwith water (200 ml), 5% sodium bicarbonate solution and 5% coppersulphate solution. It was dried over sodium sulphate and the solvent wasdistilled off to yield crude product, which was purified by columnchromatography using mixture of hexane:ethyl acetate to get dibromoAspirin dimer (11 grams) as light yellow syrup. The pure product wascharacterized by ¹H NMR (CDCl₃) δ 1.55 (m, 2H, CH₂), 1.75 (m, 2H, CH₂),1.90 (m, 2H, CH₂), 2.65 (t, 2H, CH₂), 3.40 (t, 2H, CH₂), 4.40 (s, 2H,CH₂), 4.72 (s, 2H, CH₂), 4.90 (s, 2H, CH₂), 7.10 (d, 1H, Ar), 7.35 (t,1H, Ar), 7.70 (t, 1H, Ar), 8.10 (d, 1H, Ar).

EXAMPLE 43 Synthesis of Dinitro Aspirin Dimer

To a solution of dibromo Aspirin dimer (9 grams) in acetonitrile (150ml) at 0° C. was added silver nitrate (5.1 grams) and stirred at roomtemperature for three hours followed by heating at 50° C. for 5 hours.The reaction mixture was filtered and washed with acetonitrile and driedover sodium sulphate. The solvent was distilled off and the crude wastaken into chloroform. The salts were filtered off and washed with waterand dried over sodium sulphate. The solvent was distilled off underreduced pressure and the residue was purified by column chromatographyusing a mixture of hexane: ethyl acetate to yield 6 grams of dinitroAspirin dimer as light yellow syrup. The pure product was characterizedby ^(I)H NMR (CDCl₃) δ 1.55 (m, 2H, CH₂), 1.70 (m, 4H, CH₂ X₂), 2.10 (t,2H, CH₂), 4.35 (s, 2H, CH₂), 4.45 (t, 2H, CH₂), 4.70 (s, 2H, CH₂), 4.90(s, 2H, CH₂), 7.05 (d, 1H, Ar), 7.35 (t, 1H, Ar), 7.55 (t, 1H, Ar), 8.15(d, 1H, Ar).

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention.

1. Pendant polymer or oligomer providing monomer according to formula Bor C:

wherein: A and B are independently —OH, —NH₂ or —CO₂H; L is —O—, —COO—or —NH—; D is: together or separately from L, a biologically activesubstance; P is one of —[—X—]_(p)— or —[—Y—]_(p)—, wherein p isindependently an integer from 1 to 20 inclusive; 1 or more independentlyselected repeats X are: —CH₂COO— (glycolic acid moiety); —CH(CH₃)COO—(lactic acid moiety); —CH₂CH₂OCH₂COO— (dioxanone moiety);—CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety); —(CH₂)_(y)COO— where y isone of the numbers 2, 3 or 4, or a number from 6 to 24 inclusive; or—(CH₂CH₂O)_(z)CH₂COO— where z is an integer between 2-24, inclusive; 0or more independently selected repeats X are: any other repeat that ispolyester polymerization compatible with the above recited repeats X;the order and composition of repeats X is selected to provide a desireddegradation of moiety -L-P—R; 1 or more independently selected repeats Yare: —COCH₂O— (glycolic ester moiety); —COCH(CH₃)O— (lactic estermoiety); —COCH₂OCH₂CH₂O— (dioxanone ester moiety); —COCH₂CH₂CH₂CH₂CH₂O—(caprolactone ester moiety); —CO(CH₂)_(m)O— where m is one of thenumbers 2, 3 or 4, or a number from 6 to 24 inclusive; or,—COCH₂O(CH₂CH₂O)_(n)— where n is integer between 2-24 inclusive; 0 ormore independently selected repeats Y are: any other repeat that ispolyester polymerization compatible with the above recited repeats Y;the order and composition of repeats Y is selected to provide a desireddegradation of moiety -L-P—R; and R is according to one of theapplicable following options (a) or (b): (a) where P is —[—X—]_(p), Rcan be an alkyl group, aryl, alkyl-aryl, an alicyclic group oralkyl-alicyclic, substituted with one or more —O—NO₂; and (b) where P is—[—Y—]_(p), R can be —NO₂; L′ is L with opposite orientation, and D′ isD, where D is a biologically active substance, and the linkage L′-P ischemically consistent with the recitations for L-P; L″ is L, P′ is P,and R′ is R; and E is a moiety consisting of C, H, O, S or N,predominantly of composed of C and H; wherein: if Y comprises—CH₂CH₂CH₂CH₂CH₂COO— or —COCH₂CH₂CH₂CH₂CH₂O—, then p is an integer from2 to 100 inclusive; if L is —COO—, then the corresponding P is—[—X—]_(p)—, and the last repeat X lacks the terminal O and L′ is —O— or—NH—; and if L is —NH—, then the corresponding P is —[—Y—]_(p)—, and thelast repeat Y lacks the terminal O and L′ is —O— or —OC(O)—.
 2. Apendant polymer or oligomer providing monomer according to claim 1,wherein the biologically active substances are selected from the groupconsisting of phenols, thiophenols, naphthols, flavonoids,isoflavonoids, coumarins, chromones, chalcones, cinnamic acids, benzoicacids, acetophenones, benzophenones, alkaloids, catechins, catechols,aminoalcohols, aminosalicyclic acids, hydrocinnamic acids, phenolicacids, resorcinols, indoles and hydroquinones.
 3. A compositioncomprising a polymer or oligomer covalently incorporating a pendantpolymer of claim 1 and a pharmaceutically acceptable excipient.
 4. Animplantable medical device comprising a polymer or oligomer covalentlyincorporating a pendant polymer of claim 1 and an admixed polymer. 5.The implantable medical device of claim 4, wherein the device is astent, suture, surgical staple, mesh or bone screw.
 6. A coatingcomposition for an implantable device, comprising a polymer or oligomercovalently incorporating a pendant polymer of claim 1 and an admixedpolymer.
 7. A pendant polymer or oligomer providing monomer according toclaim 1, wherein E has a molecular weight of 600 or less.
 8. A pendantpolymer or oligomer providing monomer according to claim 1, wherein Ehas a molecular weight of 500 or less.
 9. A pendant polymer or oligomerproviding monomer according to claim 1, wherein E has a molecular weightof 400 or less.
 10. The Pendant polymer or oligomer of claim 1, whereinmonomer is one of the following:


11. A composition comprising a polymer or oligomer covalentlyincorporating a pendant polymer of claim 10 and a pharmaceuticallyacceptable excipient.
 12. An implantable medical device comprising apolymer or oligomer covalently incorporating a pendant polymer of claim10 and an admixed polymer.
 13. The implantable medical device of claim12, wherein the device is a stent, suture, surgical staple, mesh or bonescrew.
 14. A coating composition for an implantable device, comprising apolymer or oligomer covalently incorporating a pendant polymer of claim10 and an admixed polymer.